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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Zamaporvint
Zamaporvint
RXC004, PHASE 2
1H-IMIDAZOLE-1-ACETAMIDE, 5-METHYL-N-(5-(2-PYRAZINYL)-2-PYRIDINYL)-4-(2-(TRIFLUOROMETHYL)-4-PYRIDINYL)-
5-METHYL-N-(5-(2-PYRAZINYL)-2-PYRIDINYL)-4-(2-(TRIFLUOROMETHYL)-4-PYRIDINYL)-1H-IMIDAZOLE-1-ACETAMIDE
UNII
M56M7CHN8E |
| Molecular Weight | 439.39 |
|---|---|
| Formula | C21H16F3N7O |
| CAS No. | 1900754-56-4 |
Zamaporvint (RXC004) is an orally active and selective inhibitor of Wnt. Zamaporvint targete membrane-bound o-acyltransferase Porcupine and inhibited Wnt ligand palmitoylation, secretion, and pathway activation. Zamaporvint displays a favorable pharmacokinetic profile and shows potent antiproliferative effects in Wnt ligand-dependent colorectal and pancreatic cell lines. Zamaporvint possesses multiple antitumor mechanisms and can be used in cancer research.
SCHEME
PATENT
Redx Pharma PLC
WO2016055786
Example 9: 2-[5-methyl-4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]-N-(5-pyrazin-2- yl-2-pyridyl)acetamide
To a stirred solution of lithium 2-[5-methyl-4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]acetate (1.04g, 3.57mmol) and 5-pyrazin-2-ylpyridin-2-amine (738mg, 4.29mmol) in THF (35mL) was added Ν,Ν-diisopropylethylamine (1.56mL, 8.93mmol) and propylphosphonic anhydride (6.38mL, 10.7mmol) and the resulting solution heated to 70°C. Reaction was monitored by LCMS and after 2 hrs further propylphosphonic anhydride (2.13mL, 3.57mmol) and N,N-diisopropylethylamine (0.6mL) were added the solution was allowed to cool to room temperature and stirred over the weekend. The solution was diluted with water and EtOAc and partitioned. The aqueous was washed with EtOAc (x2) before the combined organics were washed with brine. Product precipitated and was isolated by filtration and loaded onto a MeOH primed 10g SCX cartridge, washing with MeOH and eluting with 1 M NH3 MeOH solution. The ammonia methanol solution was concentrated to dryness in vacuo to afford an off white solid which was then dried in a vacuum oven for 2hrs. The organics were separated from the filtrate, dried (sodium sulphate), filtered and concentrated to dryness in vacuo to afford a light brown foam containing product of ~95% purity. This was dissolved in DCM and purified by flash column chromatography (25g SiO2, 70-100% EtOAc in heptane, then 0-5% MeOH/EtOAc). Appropriate fractions were combined and concentrated to dryness in vacuo to afford an off white solid. The solids were combined to give 2-[5-methyl-4-[2-(trifluoromethyl)-4-pyridyl]imidazol-1-yl]-N-(5-pyrazin-2-yl-2-pyridyl)acetamide (1.22g, 2.77mmol, 78% yield) as an off white solid.
MS Method 2: RT: 1.45 min, ES+ m/z 440.1 [M+H]+
1H NMR (400MHz, DMSO) δ/ppm: 11.27 (bs, 1 H), 9.32-9.33 (d, J=1.6Hz, 1 H), 8.70-8.75 (m, 2H), 8.64-8.65 (d, J=2.4Hz, 1 H), 8.54-8.58 (dd, J=2.4, 8.8Hz, 1 H), 8.17-8.19 (d, J=9.2Hz, 1 H), 8.09 (s, 1 H), 7.92-7.94 (d, J=4.4Hz, 1 H), 7.85 (s, 1 H), 5.12 (s, 2H), 2.45 (s, 3H).
/////////Zamaporvint, RXC004, RX C004, PHASE 2
ATICAPRANT
ATICAPRANT
1174130-61-0
BENZAMIDE, 4-(4-(((2S)-2-(3,5-DIMETHYLPHENYL)-1-PYRROLIDINYL)METHYL)PHENOXY)-3-FLUORO-
C26H27FN2O2, 418.512
- 4-[4-[[(2S)-2-(3,5-Dimethylphenyl)-1-pyrrolidinyl]methyl]phenoxy]-3-fluorobenzamide (ACI)
- (S)-4-(4-((2-(3,5-Dimethylphenyl)pyrrolidin-1-yl)methyl)phenoxy)-3-fluorobenzamide
- 4-(4-{[(2S)-2-(3,5-dimethylphenyl)pyrrolidin-1-yl]methyl}phenoxy)-3-fluorobenzamide
- Aticaprant
- CERC 501
- JNJ 67953964
- JNJ 67953964AAA
- LY 2456302
- S-Aticaprant
- CERC-501
- JSPA 0658 JSPA-0658 JSPA0658
- LY 2456302 LY-2456302 , LY2456302
- OriginatorEli Lilly and Company
- DeveloperAvalo Therapeutics; Eli Lilly and Company; Johnson & Johnson Innovative Medicine
- ClassAntidepressants; Benzamides; Benzene derivatives; Drug withdrawal therapies; Fluorinated hydrocarbons; Pyrrolidines; Smoking cessation therapies
- Mechanism of ActionOpioid kappa receptor antagonists
- Phase III Major depressive disorder
- DiscontinuedAlcoholism; Cocaine-related disorders; Smoking withdrawal
- 26 Jun 2024Janssen Research & Development initiates a phase III VENTURA-7 trial for Major depressive disorder (Adjunctive treatment) in USA (PO, Tablet) (NCT06514742) (EudraCT2024-511557-21-00)
- 01 Oct 2023Janssen Pharmaceuticals is now called Johnson & Johnson Innovative Medicine (Janssen Pharmaceuticals website, October 2023)
- 19 May 2023Chemical structure information added
Aticaprant, also known by its developmental codes JNJ-67953964, CERC-501, and LY-2456302, is a κ-opioid receptor (KOR) antagonist which is under development for the treatment of major depressive disorder.[2][3][4] A regulatory application for approval of the medication is expected to be submitted by 2025.[2] Aticaprant is taken by mouth.[1]
Side effects of aticaprant include itching, among others.[4][5] Aticaprant acts as a selective antagonist of the KOR, the biological target of the endogenous opioid peptide dynorphin.[3] The medication has decent selectivity for the KOR over the μ-opioid receptor (MOR) and other targets, a relatively long half-life of 30 to 40 hours, and readily crosses the blood–brain barrier to produce central effects.[4][6]
Aticaprant was originally developed by Eli Lilly, was under development by Cerecor for a time, and is now under development by Janssen Pharmaceuticals.[2] As of July 2022, it is in phase 3 clinical trials for major depressive disorder.[2] Like other kappa opioid antagonists currently under clinical investigation for the treatment of major depression, its efficacy may be compromised by the countervailing activation of pro-inflammatory cytokines in microglia within the CNS.[7]
Aticaprant was also under development for the treatment of alcoholism, cocaine use disorder, and smoking withdrawal, but development for these indications was discontinued.[2]
Pharmacology
Pharmacodynamics
Aticaprant is a potent, selective, short-acting (i.e., non-“inactivating”) antagonist of the KOR (Ki = 0.81 nM vs. 24.0 nM and 155 nM for the μ-opioid receptor (MOR) and δ-opioid receptor (DOR), respectively; approximately 30-fold selectivity for the KOR).[8][9][10] The drug has been found to dose-dependently block fentanyl-induced miosis at 25 mg and 60 mg in humans (with minimal to no blockade at doses of 4 to 10 mg), suggesting that the drug significantly occupies and antagonizes the MOR at a dose of at least 25 mg but not of 10 mg or less.[10] However, a more recent study assessing neuroendocrine effects of the drug in normal volunteers and subjects with a history of cocaine dependence reported observations consistent with modest MOR antagonism at the 10 mg dose.[11] In animal models of depression, aticaprant has been found to have potent synergistic efficacy in combination with other antidepressants such as citalopram and imipramine.[12]
Positron emission tomography imaging revealed that brain KORs were almost completely saturated by the drug 2.5 hours following a single dose of 10 mg, which supported the 4 mg to 25 mg dosages that aticaprant is being explored at in clinical trials.[13][14] Occupancy was 35% for a 0.5 mg dose and 94% for a 10 mg dose.[15][14] At 24 hours post-dose, receptor occupancy was 19% for 0.5 mg and 82% for 25 mg.[15][14] No serious side effects were observed, and all side effects seen were mild to moderate and were not thought to be due to aticaprant.[14]
Pharmacokinetics
The oral bioavailability of aticaprant is 25%.[1] The drug is rapidly absorbed, with maximal concentrations occurring 1 to 2 hours after administration.[1] It has an elimination half-life of 30 to 40 hours in healthy subjects.[1] The circulating levels of aticaprant increase proportionally with increasing doses.[1] Steady-state concentrations are reached after 6 to 8 days of once-daily dosing.[1] Aticaprant has been shown to reproducibly penetrate the blood–brain barrier.[13][14]
History
Aticaprant was originally developed by Eli Lilly under the code name LY-2456302.[2] It first appeared in the scientific literature in 2010 or 2011.[16][17] The compound was first patented in 2009.[18]
In February 2015, Cerecor Inc. announced that they had acquired the rights from Eli Lilly to develop and commercialize LY-2456302 (under the new developmental code CERC-501).[19]
As of 2016, aticaprant has reached phase II clinical trials as an augmentation to antidepressant therapy for treatment-resistant depression.[20][12] A phase II study of aticaprant in heavy smokers was commenced in early 2016 and results of the study were expected before the end of 2016.[14] Aticaprant failed to meet its main endpoint for nicotine withdrawal in the study.[21]
In August 2017, it was announced that Cerecor had sold its rights to aticaprant to Janssen Pharmaceuticals.[22][21] Janssen was also experimenting with esketamine for the treatment of depression as of 2017.[21]
Research
In addition to major depressive disorder, aticaprant was under development for the treatment of alcoholism, cocaine use disorder, and smoking withdrawal.[2] However, development for these indications was discontinued.[2]
See also
κ-Opioid receptor § Antagonists
SCHEME
SYNTHESIS
WO/2024/178082COMPOSITION OF OPIOID RECEPTOR MODULATOR AND MDMA FOR USE THEREOF
WO/2024/173843QUINOLINE DERIVATIVES WHICH ACT AS KAPPA-OPIOID RECEPTOR ANTAGONISTS
20240238245COMPOSITIONS AND METHODS FOR THE TREATMENT OF DEPRESSION
20240189274Compositions And Methods For The Treatment Of Depression
WO/2024/102802ZELATRIAZIN FOR THE TREATMENT OF DEPRESSION
WO/2024/100285TREATMENT OF A COGNITIVE DISORDER WITH AN AGENT THAT INCREASES THE..
117615757Compositions and methods for treating depression
117142999Racemization method of drug intermediate
20230348377PURE FORMS OF CRYSTALLINE ATICAPRANT
WO/2023/170550POLYMORPH FORMS OF ATICAPRANT FOR USE IN TREATING MAJOR DEPRESSIVE DISORDER
WO/2023/170547PURE FORMS OF CRYSTALLINE ATICAPRANT
20230277499Forms of aticaprant
20230277500COMPOSITIONS COMPRISING ATICAPRANT
WO/2023/164385NEUROACTIVE STEROIDS FOR TREATMENT OF GASTROINTESTINAL DISEASES OR CONDITIONS
20090186873Kappa selective opioid receptor antagonist
WO/2009/094260KAPPA SELECTIVE OPIOID RECEPTOR ANTAGONIST
20100197669Kappa selective opioid receptor antagonist
2252581KAPPA SELECTIVE OPIOID RECEPTOR ANTAGONIST
201500053151-substituted 4-arylpiperazine as kappa opioid receptor antagonists
WO/2013/0864961-SUBSTITUTED 4-ARYLPIPERAZINE AS KAPPA OPIOID RECEPTOR ANTAGONISTS
101925576Kappa selective opioid receptor antagonist
PAPERS
ACS Omega (2020), 5(41), 26938-26945 https://pubs.acs.org/doi/full/10.1021/acsomega.0c04329
REF https://pubs.acs.org/doi/suppl/10.1021/acsomega.0c04329/suppl_file/ao0c04329_si_001.pdf
N-Methoxy-N-methyl-4-chlorobutyramide (S1). To a mixture of N,O-dimethylhydroxylamine hydrochloride (95.0 mmol, 9.27 g) in CH2Cl2 (150 mL) was
added 2 M NaOH (300 mmol, 150 mL) and 4-chlorobutyryl chloride (100 mmol,
11.2 mL) at 0 ˚C. The mixture was stirred for 42 h at room temperature. The
organic phase was separated, and the aqueous phase was extracted with CH2Cl2 (2 × 50 mL). The combined organic phase was washed with 2 M NaOH (100 mL), dried over Na2SO4, filtered, and concentrated
to afford the title comlund in 75% yield as a colorless liquid.
1H NMR (400 MHz, CDCl3) : 2.08-2.15
(m, 2H), 2.63 (t, J = 7.0 Hz, 2H), 3.19 (s, 3H), 3.64 (t, J = 6.3 Hz, 2H), 3.71 (s, 3H).
13C{
1H} NMR (100
MHz, CDCl3) : 27.1, 28.6, 32.1, 44.6, 61.1. IR (max/cm-1
): 2965, 2940, 2821, 1656, 14421, 1417, 1387,
1178, 1107, 997. HRMS (ESI+): calculated for [M+Na]+
: 188.0449, found: 188.0450.
4-Chloro-1-(3,5-dimethylphenyl)butan-1-one (S2). To a mixture of N-methoxy-N-methyl-4-chlorobutyramide (S1, 65.0 mmol, 10.8 g) in anhydrous Et2O
(100 mL) was added dropwise 3,5-dimethylphenylmagnesium bromide (ca. 1 M
in Et2O, ca. 130 mmol, prepared from 1-bromo-3,5-dimethylbenzene (130 mmol,
17.7 mL) and Mg turnings (169 mmol, 4.11 g) in anhydrous Et2O (130 mL)) over 1 h at -40 ˚C under Ar.
The reaction mixture was stirred at room temperature for 20 h. After cooling to 0 ˚C, saturated NH4Cl
solution (200 mL) was added. The organic phase was separated, washed with water (100 mL) and brine
(100 mL), dried over Na2SO4, and filtered. After concentration, the residue was purified by column chromatography (silica gel, hexane/EtOAc as eluent) to afford the title compound in 91% yield as a greenish
yellow liquid.
1H NMR (400 MHz, CDCl3) : 2.18-2.25 (m, 2H), 2.38 (s, 6H), 3.15 (t, J = 7.0 Hz, 2H),
3.67 (t, J = 6.3 Hz, 2H), 7.21 (s, 1H), 7.58 (s, 2H). 13C{
1H} NMR (100 MHz, CDCl3) : 21.2, 26.8, 35.4,
44.7, 125.8, 134.8, 136.8, 138.3, 199.4. IR (max/cm-1
): 3047, 3006, 2961, 2920, 2868, 1443, 1411, 1322,
1303, 1181, 1159, 844, 785, 687. HRMS (APCI+): calculated for [M+H]+
: 211.0884, found: 211.0884.
(RS)-N-(4-Chloro-1-(3,5-dimethylphenyl)butylidene)-tertbutanesulfinamide (S3). Ti(OEt)4 (100 mol, 21.0 mL) was added to a mixture
of (RS)-tert-butanesulfinamide (1.0 M in THF, 50 mmol, 50 mL) and 4-chloro1-(3,5-dimethylphenyl)butan-1-one (S2, 50.0 mmol, 10.5 g) under N2. The mixture was refluxed for 48 h. After cooling to room temperature, brine (100 mL)
was added, and the resulting mixture was filtered over Celite using EtOAc (ca.
300 mL). The organic was separated, dried over Na2SO4, and filtered. After concentration under reduced
pressure, the residue was purified by column chromatography (silica gel, hexane/EtOAc as eluent) to
afford the title compound in 57% yield as a brown viscous liquid.
1H NMR (400 MHz, CDCl3) : 1.33
(s, 9H), 2.10-2.22 (m, 2H), 2.36 (s, 6H), 3.27 (s, 1H), 3.43 (s, 1H), 3.64 (t, J = 6.5 Hz, 2H), 7.13 (s, 1H),
7.47 (s, 2H).
13C{
1H} NMR (100 MHz, CDCl3) : 21.3, 22.7, 30.2, 31.6, 44.7, 57.7, 125.2, 133.4, 137.6,
138.2, 178.6. IR (max/cm-1
): 3046, 2958, 2922, 2866, 1599, 1577, 1455, 1361, 1320, 1308, 1069, 856.
HRMS (ESI+): calculated for [M+H]
+
: 314.1340, found: 314.1344. []D
20 +11.0 (c = 1.01, CH2Cl2).
(RS,S)-1-tert-Butylsulfinyl-2-(3,5-dimethylphenyl)pyrrolidine (S4). To a solution of (RS)-N-(4-chloro-1-(3,5-dimethylphenyl)butylidene)-tert-butanesulfinamide
(S3, 25.6 mmol, 8.06 g) in anhydrous THF (100 mL) at -78 °C was added LiBEt3H
(28 mmol, 0.5 M in THF, 28.2 mL) under Ar. The reaction was stirred at -78 °C for
1 h, subsequently allowed to warm up to room temperature and stirred for additional
20 h. Saturated NaHCO3 solution (80 mL) was slowly added. The mixture was filtered and extracted
with EtOAc (3 × 100 mL). The combined organic phase was dried over Na2SO4 and filtered. After
concentration, the residue was purified by column chromatography (silica gel, hexane/EtOAc as eluent)
to afford the title compound in 72% yield as pale yellow solid. mp.: 56 ˚C. 1H NMR (400 MHz, CDCl3)
: 1.12 (s, 9H), 1.74-1.90 (m, 3H), 1.93-2.02 (m, 1H), 2.18-2.27 (m, 1H), 2.30 (s, 6H), 2.94-3.02 (m, 1H),
3.85-3.91 (m, 1H), 4.55-4.59 (m, 1H), 6.88 (s, 1H), 6.90 (s, 2H).
13C{
1H} NMR (100 MHz, CDCl3) :
21.3, 23.8, 26.3, 36.0, 42.1, 57.2, 69.2, 125.0, 128.7, 137.7, 143.2. IR (max/cm-1
): 3023, 2957, 2920,
2866, 1607, 1471, 1360, 1061, 957, 847. HRMS (ESI+): calculated for [M+Na]+
: 302.1549, found:
302.1548. []D
20
-137 (c = 0.49, CH2Cl2)
(S)-2-(3,5-Dimethylphenyl)pyrrolidine hydrochloride (1j•HCl). To a solution
of (RS,S)-1-tert-butylsulfinyl-2-(3,5-dimethylphenyl)pyrrolidine (S4, 14.7 mmol,
4.12 g) in dioxane (250 mL) was added dropwise HCl (ca. 150 mmol, 4 M in dioxane, 38 mL). The mixture was stirred for 1 h at room temperature under N2, and
then the mixture was concentrated under reduced pressure. Then, Et2O (200 mL) was added to the residue
and the mixture was cooled to 0 ˚C. The precipitate was collected by filtration, washed with Et2O (40
mL), and dried under reduced pressure to afford the title compound in 94% yield as white solid. mp.: 198
˚C. 1H NMR (400 MHz, D2O) : 2.00-2.15 (m, 3H), 2.18 (s, 6H), 2.27-2.35 (m, 1H), 3.27-3.36 (m, 2H),
4.45 (t, J = 8.0 Hz, 1H), 6.97 (s, 2H), 7.01 (s, 1H). 13C{
1H} NMR (100 MHz, D2O) : 20.9, 24.19, 30.9,
46.0, 63.8, 119.79, 125.6, 131.4, 135.3, 140.1. IR (max/cm-1
): 3033, 3012, 2970, 2855, 2743, 2571, 2480,
1608, 1590, 1414, 850. HRMS (ESI+): calculated for [M-Cl]
+
: 176.1434, found: 176.1435. []D
20 +7.1
(c = 1.01, MeOH).
(S)-2-(3,5-Dimethylphenyl)pyrrolidine (1j). To a suspension of (S)-2-(3,5-dimethylphenyl)pyrrolidine hydrochloride (1j•HCl, 13.5 mmol, 2.86 g) in anhydrous Et2O
(200 mL) was added a saturated solution of NaHCO3 (200 mL). The resulting mixture
was stirred for 20 min at room temperature. The organic was separated and the aqueous
phase was extracted with Et2O (2 × 100 mL). The combined organic phase was dried over MgSO4 and
filtered. The solvent was removed under reduced pressure to afford the title compound as a pale yellow
liquid in 99% yield.
1H NMR (400 MHz, CDCl3) : 1.60-1.71 (m, 1H), 1.78-1.96 (m, 2H), 1.98 (s, 1H),
2.11-2.19 (m, 1H), 2.30 (s, 6H), 2.95-3.02 (m, 1H), 3.17-3.23 (m, 1H), 4.03 (t, J = 7.7 Hz, 1H), 6.87 (s,
1H), 6.97 (s, 2H). 13C{
1H} NMR (100 MHz, CDCl3) : 21.3, 25.5, 34.2, 46.9, 62.6, 124.2, 128.4, 137.8,
144.7. IR (max/cm-1
): 3332, 3010, 2960, 2915, 2869, 1605, 1458, 1101, 845. HRMS (ESI+): calculated
for [M+H]+
: 176.1434, found: 176.1436. []D
20
-30.5 (c = 1.01, MeOH). Chiral HPLC (ChiralPak ODH, 4.6 mm × L 250 mm, hexane:2-propanol = 90:10, 0.5 mL/min, = 254 nm): tR/min = 18.7 (1%),
19.8 (99%).
3-Fluoro-4-(4-formylphenoxy)benzonitrile2
(S5). A mixture of 3,4-
difluorobenzonitrile (35.0 mmol, 4.87 g), 4-hydroxybenzaldehyde (35.0
mmol, 4.27 g), and K2CO3 (70.0 mmol, 9.67 g) in N,N-dimethylacetamide
(90 mL) was stirred at 100 ˚C for 2 h under N2. After cooling, the reaction
mixture was poured into ice water. White precipitate was collected by filtration, washed with water, and dried under reduced pressure to afford the title compound as pale yellow
solid in 82% yield. mp.: 101 ˚C. 1H NMR (400 MHz, CDCl3) : 7.11-7.15 (m, 2H), 7.20 (t, J = 8.2 Hz,
1H), 7.49-7.51 (m, 1H), 7.54 (dd, J = 9.7, 1.9 Hz, 1H), 7.91-7.94 (m, 2H), 9.98 (s, 1H).
13C{
1H} NMR
(100 MHz, CDCl3) : 109.1 (d, 3
JC-F = 8.2 Hz), 117.1 (d, 4
JC-F = 2.5 Hz), 117.9, 121.3 (d, 2
JC-F = 21.3 Hz),
122.5 (d, 4
JC-F = 1.6 Hz), 129.6 (d, 3
JC-F = 4.1 Hz), 132.1, 132.7, 147.0 (d, 2
JC-F = 11.5 Hz), 153.6 (d, 1
JCF = 254.8 Hz), 160.7, 190.4. IR (max/cm-1
): 3100, 3060, 2846, 2812, 2761, 2232, 1697, 1687, 1585, 1497,
1277, 1216, 1166, 1114, 836. HRMS (APCI+): calculated for [M+H]+
: 242.0612, found: 242.0616.
3-Fluoro-4-(4-formylphenoxy)benzamide2
(2f). To a mixture of 3-
fluoro-4-(4-formylphenoxy)benzonitrile (S5, 26.0 mmol, 6.27 g) and
K2CO3 (13.0 mmol, 1.80 g) in DMSO (24 mL) was added dropwise 35%
H2O2 (ca. 29 mmol, 3.1 mL) at 10 ˚C over 5 min. The reaction mixture
was stirred at room temperature for 2 h. The reaction mixture was
poured into ice water. White precipitate was collected by filtration, washed with water, and dried under
reduced pressure to afford the title compound as white solid in 92% yield. mp. 129 ˚C. 1H NMR (400
MHz, (D3C)2SO) : 9.96 (s, 1H), 8.12 (s, 1H), 7.96 (d, J = 8.2 Hz, 2H), 7.93 (dd, J = 1.9, 10.0 Hz, 1H),
7.85-7.82 (m, 1H), 7.58 (s, 1H), 7.42 (t, J = 8.2 Hz, 1 H), 7.20 (d, J = 8.2 Hz, 2H).
13C{
1H} NMR (100
MHz, (D3C)2SO) : 116.6 (d, 2
JC-F = 19.7 Hz), 116.9, 122.6, 125.1 (d, 4
JC-F = 3.3 Hz), 131.9 (d, 2
JC-F =
21.3 Hz), 132.1, 132.7 (d, 3
JC-F = 5.7 Hz), 143.7 (d, 3
JC-F = 12.3 Hz), 153.1 (d, 1
JC-F = 248.2 Hz), 161.3,
165.8, 191.5. IR (max/cm-1
): 3356, 3185, 2844, 1668, 1598, 1504, 1433, 1382, 1269, 1218, 1156, 1128,
- HRMS (ESI+): calculated for [M+Na]
+
: 282.0537, found: 282.0541. HRMS (APCI+): calculated
for [M+H]+
: 260.0717, found: 260.0716.
NEXT
Reaction Chemistry & Engineering (2022), 7(8), 1779-1785
Journal of Medicinal Chemistry (2011), 54(23), 8000-8012
| Clinical data | |
|---|---|
| Other names | JNJ-67953964; CERC-501; LY-2456302 |
| Routes of administration | By mouth[1] |
| Pharmacokinetic data | |
| Bioavailability | 25%[1] |
| Elimination half-life | 30–40 hours[1] |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 1174130-61-0 |
| PubChem CID | 44129648 |
| IUPHAR/BPS | 9194 |
| DrugBank | DB12341 |
| ChemSpider | 28424203 |
| UNII | DE4G8X55F5 |
| KEGG | D11831 |
| ChEMBL | ChEMBL1921847 |
| CompTox Dashboard (EPA) | DTXSID90151777 |
| Chemical and physical data | |
| Formula | C26H27FN2O2 |
| Molar mass | 418.512 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
References
^ Jump up to:a b c d e f g h i Li W, Sun H, Chen H, Yang X, Xiao L, Liu R, et al. (2016). “Major Depressive Disorder and Kappa Opioid Receptor Antagonists”. Translational Perioperative and Pain Medicine. 1 (2): 4–16. PMC 4871611. PMID 27213169.
- ^ Jump up to:a b c d e f g h “CERC 501”. Adis Insight. 30 January 2018.
- ^ Jump up to:a b Browne CA, Wulf H, Lucki I (2022). “Kappa Opioid Receptors in the Pathology and Treatment of Major Depressive Disorder”. In Liu-Chen LY, Inan S (eds.). The Kappa Opioid Receptor. Handbook of Experimental Pharmacology. Vol. 271. pp. 493–524. doi:10.1007/164_2020_432. ISBN 978-3-030-89073-5. PMID 33580854. S2CID 231908782.
- ^ Jump up to:a b c Reed B, Butelman ER, Kreek MJ (2022). “Kappa Opioid Receptor Antagonists as Potential Therapeutics for Mood and Substance Use Disorders”. In Liu-Chen LY, Inan S (eds.). The Kappa Opioid Receptor. Handbook of Experimental Pharmacology. Vol. 271. pp. 473–491. doi:10.1007/164_2020_401. ISBN 978-3-030-89073-5. PMID 33174064. S2CID 226305229.
- ^ Krystal AD, Pizzagalli DA, Smoski M, Mathew SJ, Nurnberger J, Lisanby SH, et al. (May 2020). “A randomized proof-of-mechanism trial applying the ‘fast-fail’ approach to evaluating κ-opioid antagonism as a treatment for anhedonia”. Nature Medicine. 26 (5): 760–768. doi:10.1038/s41591-020-0806-7. PMC 9949770. PMID 32231295. S2CID 256839849.
- ^ Dhir A (January 2017). “Investigational drugs for treating major depressive disorder”. Expert Opinion on Investigational Drugs. 26 (1): 9–24. doi:10.1080/13543784.2017.1267727. PMID 27960559. S2CID 45232796.
- ^ Missig G, Fritsch EL, Mehta N, Damon ME, Jarrell EM, Bartlett AA, et al. (January 2022). “Blockade of kappa-opioid receptors amplifies microglia-mediated inflammatory responses”. Pharmacology, Biochemistry, and Behavior. 212: 173301. doi:10.1016/j.pbb.2021.173301. PMC 8748402. PMID 34826432.
- ^ Rorick-Kehn LM, Witkin JM, Statnick MA, Eberle EL, McKinzie JH, Kahl SD, et al. (February 2014). “LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders”. Neuropharmacology. 77: 131–144. doi:10.1016/j.neuropharm.2013.09.021. PMID 24071566. S2CID 3230414.
- ^ Lowe SL, Wong CJ, Witcher J, Gonzales CR, Dickinson GL, Bell RL, et al. (September 2014). “Safety, tolerability, and pharmacokinetic evaluation of single- and multiple-ascending doses of a novel kappa opioid receptor antagonist LY2456302 and drug interaction with ethanol in healthy subjects”. Journal of Clinical Pharmacology. 54 (9): 968–978. doi:10.1002/jcph.286. PMID 24619932. S2CID 14814449.
- ^ Jump up to:a b Rorick-Kehn LM, Witcher JW, Lowe SL, Gonzales CR, Weller MA, Bell RL, et al. (October 2014). “Determining pharmacological selectivity of the kappa opioid receptor antagonist LY2456302 using pupillometry as a translational biomarker in rat and human”. The International Journal of Neuropsychopharmacology. 18 (2): pyu036. doi:10.1093/ijnp/pyu036. PMC 4368892. PMID 25637376.
- ^ Reed B, Butelman ER, Fry RS, Kimani R, Kreek MJ (March 2018). “Repeated Administration of Opra Kappa (LY2456302), a Novel, Short-Acting, Selective KOP-r Antagonist, in Persons with and without Cocaine Dependence”. Neuropsychopharmacology. 43 (4): 928. doi:10.1038/npp.2017.245. PMC 5809790. PMID 29422497.
- ^ Jump up to:a b Urbano M, Guerrero M, Rosen H, Roberts E (May 2014). “Antagonists of the kappa opioid receptor”. Bioorganic & Medicinal Chemistry Letters. 24 (9): 2021–2032. doi:10.1016/j.bmcl.2014.03.040. PMID 24690494.
- ^ Jump up to:a b “Publication Reports Human Brain Penetration and Target Engagement of Cerecor’s Oral Kappa Opioid Receptor Antagonist, CERC-501”. BusinessWire. 11 December 2015.
- ^ Jump up to:a b c d e f Naganawa M, Dickinson GL, Zheng MQ, Henry S, Vandenhende F, Witcher J, et al. (February 2016). “Receptor Occupancy of the κ-Opioid Antagonist LY2456302 Measured with Positron Emission Tomography and the Novel Radiotracer 11C-LY2795050”. The Journal of Pharmacology and Experimental Therapeutics. 356 (2): 260–266. doi:10.1124/jpet.115.229278. PMC 4727157. PMID 26628406.
- ^ Jump up to:a b Placzek MS (August 2021). “Imaging Kappa Opioid Receptors in the Living Brain with Positron Emission Tomography”. In Liu-Chen LY, Inan S (eds.). The Kappa Opioid Receptor. Handbook of Experimental Pharmacology. Vol. 271. pp. 547–577. doi:10.1007/164_2021_498. ISBN 978-3-030-89073-5. PMID 34363128. S2CID 236947969.
- ^ Zheng MQ, Nabulsi N, Kim SJ, Tomasi G, Lin SF, Mitch C, et al. (March 2013). “Synthesis and evaluation of 11C-LY2795050 as a κ-opioid receptor antagonist radiotracer for PET imaging”. Journal of Nuclear Medicine. 54 (3): 455–463. doi:10.2967/jnumed.112.109512. PMC 3775344. PMID 23353688.
- ^ Mitch CH, Quimby SJ, Diaz N, Pedregal C, de la Torre MG, Jimenez A, et al. (December 2011). “Discovery of aminobenzyloxyarylamides as κ opioid receptor selective antagonists: application to preclinical development of a κ opioid receptor antagonist receptor occupancy tracer”. Journal of Medicinal Chemistry. 54 (23): 8000–8012. doi:10.1021/jm200789r. PMID 21958337.
- ^ “WO2009094260A1 – Kappa selective opioid receptor antagonist”. Google Patents. 13 January 2009. Retrieved 29 August 2022.
- ^ “Cerecor Bolsters Clinical Pipeline with Acquisition of Phase 2-ready Kappa Opioid Receptor Antagonist from Eli Lilly and Company”. cerecor.com. February 20, 2015. Archived from the original on 2015-02-23. Retrieved March 18, 2015.
- ^ Rankovic Z, Hargreaves R, Bingham M (2012). Drug Discovery for Psychiatric Disorders. Royal Society of Chemistry. pp. 314–317. ISBN 978-1-84973-365-6.
- ^ Jump up to:a b c Bushey R (August 2017). “J&J Adds New Depression Drug to Portfolio”. Drug Discovery and Development Magazine.
- ^ “Cerecor Announces Divestiture of CERC-501 to Janssen Pharmaceuticals, Inc”. Marketwired. August 2017. Archived from the original on 2017-09-01. Retrieved 2017-09-01.
Further reading
- Carlezon WA, Krystal AD (October 2016). “Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials”. Depression and Anxiety. 33 (10): 895–906. doi:10.1002/da.22500. PMC 5288841. PMID 27699938.
- Li W, Sun H, Chen H, Yang X, Xiao L, Liu R, et al. (2016). “Major Depressive Disorder and Kappa Opioid Receptor Antagonists”. Translational Perioperative and Pain Medicine. 1 (2): 4–16. PMC 4871611. PMID 27213169.
- Dhir A (January 2017). “Investigational drugs for treating major depressive disorder”. Expert Opinion on Investigational Drugs. 26 (1): 9–24. doi:10.1080/13543784.2017.1267727. PMID 27960559. S2CID 45232796.
- Reed B, Butelman ER, Kreek MJ (2017). “Endogenous opioid system in addiction and addiction-related behaviors”. Current Opinion in Behavioral Sciences. 13: 196–202. doi:10.1016/j.cobeha.2016.12.002. ISSN 2352-1546. S2CID 53149180.
- Rakesh G, Pae CU, Masand PS (August 2017). “Beyond serotonin: newer antidepressants in the future”. Expert Review of Neurotherapeutics. 17 (8): 777–790. doi:10.1080/14737175.2017.1341310. PMID 28598698. S2CID 205823807.
- Helal MA, Habib ES, Chittiboyina AG (December 2017). “Selective kappa opioid antagonists for treatment of addiction, are we there yet?”. European Journal of Medicinal Chemistry. 141: 632–647. doi:10.1016/j.ejmech.2017.10.012. PMID 29107424.
- McHugh KL, Kelly JP (2018). “Modulation of the central opioid system as an antidepressant target in rodent models”. The Opioid System as the Interface between the Brain’s Cognitive and Motivational Systems. Progress in Brain Research. Vol. 239. pp. 49–87. doi:10.1016/bs.pbr.2018.07.003. ISBN 9780444641670. PMID 30314569.
- Bailey SJ, Husbands SM (June 2018). “Targeting opioid receptor signaling in depression: do we need selective κ opioid receptor antagonists?”. Neuronal Signaling. 2 (2): NS20170145. doi:10.1042/NS20170145. PMC 7373229. PMID 32714584.
- Chavkin C (August 2018). “Kappa-opioid antagonists as stress resilience medications for the treatment of alcohol use disorders”. Neuropsychopharmacology. 43 (9): 1803–1804. doi:10.1038/s41386-018-0046-4. PMC 6046055. PMID 29752444.
- Krystal AD, Pizzagalli DA, Mathew SJ, Sanacora G, Keefe R, Song A, et al. (December 2018). “The first implementation of the NIMH FAST-FAIL approach to psychiatric drug development”. Nature Reviews. Drug Discovery. 18 (1): 82–84. doi:10.1038/nrd.2018.222. PMC 6816017. PMID 30591715.
- Lazar MA, McIntyre RS (2019). “Novel Therapeutic Targets for Major Depressive Disorder”. Neurobiology of Depression. pp. 383–400. doi:10.1016/B978-0-12-813333-0.00034-2. ISBN 9780128133330. S2CID 86782597.
- Browne CA, Lucki I (September 2019). “Targeting opioid dysregulation in depression for the development of novel therapeutics”. Pharmacology & Therapeutics. 201: 51–76. doi:10.1016/j.pharmthera.2019.04.009. PMC 6859062. PMID 31051197.
- Banks ML (2020). “The Rise and Fall of Kappa-Opioid Receptors in Drug Abuse Research”. In Nader MA, Hurd YL (eds.). Substance Use Disorders. Handbook of Experimental Pharmacology. Vol. 258. pp. 147–165. doi:10.1007/164_2019_268. ISBN 978-3-030-33678-3. PMC 7756963. PMID 31463605.
- Browne CA, Jacobson ML, Lucki I (2020). “Novel Targets to Treat Depression: Opioid-Based Therapeutics”. Harvard Review of Psychiatry. 28 (1): 40–59. doi:10.1097/HRP.0000000000000242. PMID 31913981. S2CID 210120636.
- Jacobson ML, Browne CA, Lucki I (January 2020). “Kappa Opioid Receptor Antagonists as Potential Therapeutics for Stress-Related Disorders”. Annual Review of Pharmacology and Toxicology. 60: 615–636. doi:10.1146/annurev-pharmtox-010919-023317. PMID 31914893. S2CID 210121357.
- Mercadante S, Romualdi P (2020). “The Therapeutic Potential of Novel Kappa Opioid Receptor-based Treatments”. Current Medicinal Chemistry. 27 (12): 2012–2020. doi:10.2174/0929867326666190121142459. PMID 30666905. S2CID 58558833.
External links
Aticaprant – Eli Lilly and Company/Janssen Pharmaceuticals – AdisInsight
//////ATICAPRANT, CERC-501, JSPA 0658, JSPA-0658, JSPA0658, LY 2456302, LY-2456302, LY2456302, Phase 3, ELI LILLY, Major depressive disorder, JNJ-67953964, WHO 10582
ZASTAPRAZAN
ZASTAPRAZAN
2133852-18-1
362.5 g/mol, C22H26N4O
- 1-Azetidinyl[8-[[(2,6-dimethylphenyl)methyl]amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl]methanone (ACI)
- azetidin-1-yl-[8-[(2,6-dimethylphenyl)methylamino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl]methanone
JAQBO; JP-1366; OCN-101; Zastaprazan citrate – Onconic Therapeutics, UNII-W9S9KZX5MD
- Originator Onconic Therapeutics
- Class Anti-inflammatories; Antiulcers; Azetidines; Imidazoles; Methylamines; Pyridines; Small molecules
- Mechanism of Action Potassium-competitive acid blockers
Highest Development Phases
- Registered Erosive oesophagitis
- Phase III Gastric ulcer; Peptic ulcer
- 19 Jul 2024Onconic Therapeutics completes a phase III trial in Gastric ulcer in South Korea (PO) (NCT05448001)
- 03 Jun 2024Onconic Therapeutics plans a phase III trial for Peptic ulcer (Prevention) in South Korea (PO, Capsule) (NCT06439563)
- 29 May 2024Interim efficacy data from a phase III ZERO-1 trial in erosive esophagitis released by Onconic Therapeutics
Zastaprazan (JP-1366) is a proton pump inhibitor (WO2018008929). Zastaprazan can be used for the research of gastrointestinal inflammatory diseases or gastric acid-related diseases.
SCHEME
Patent
WO2018008929
PATENT
KR1777971
//////////ZASTAPRAZAN, JAQBO, JP-1366, OCN-101, Zastaprazan citrate, Onconic Therapeutics, Erosive oesophagitis, Phase 3, Gastric ulcer, Peptic ulcer
Deuruxolitinib
Deuruxolitinib
C17H18N6, 314.422
Fda approved Leqselvi, 7/25/2024, To treat severe alopecia areata
C-21543, CTP 543, CTP-543, CTP543
(3r)-3-(2,2,3,3,4,4,5,5-d8)cyclopentyl-3-(4-(7h-pyrrolo(2,3-d)pyrimidin-4-yl)-1h-pyrazol-1-yl)propanenitrile
1h-pyrazole-1-propanenitrile, .beta.-(cyclopentyl-2,2,3,3,4,4,5,5-d8)-4-(7h-pyrrolo(2,3-d)pyrimidin-4-yl)-, (.beta.r)-D8-ruxolitinib
| Ingredient | UNII | CAS | InChI Key |
|---|---|---|---|
| Deuruxolitinib phosphate | 8VJ43S4LCM | 2147706-60-1 | JFMWPOCYMYGEDM-NTVOUFPTSA-N |
unii
0CA0VSF91Y
Deuruxolitinib, sold under the brand name Leqselvi, is a medication used for the treatment of alopecia areata.[1] It is a Janus kinase inhibitor selective for JAK1 and JAK2.[2] Although the relative effectiveness of deuruxolitinib and another Janus kinase inhibitor—baricitinib—for alopecia areata may vary depending on the population studied, both drugs are more effective than alternative treatments.[3]
Deuruxolitinib was approved for medical use in the United States in July 2024.[1][4]
Medical uses
Deuruxolitinib is indicated for the treatment of adults with severe alopecia areata.[1]
Side effects
The FDA prescribing label for deuruxolitinib contains a boxed warning for serious infections; malignancies; cardiovascular death, myocardial infarction, and stroke; and thrombosis.[5]
Society and culture
Names
Deuruxolitinib is the international nonproprietary name[6] and the United States Adopted Name.[7]
SYN
20240108633METHOD FOR PREVENTING OR TREATING DISEASE OR CONDITION ASSOCIATED WITH ANTITUMOR AGENT
20240058345TREATMENT OF HAIR LOSS DISORDERS WITH DEUTERATED JAK INHIBITORS
2023553253重水素化ＪＡＫ阻害剤による脱毛障害の治療のためのレジメン
20230390292REGIMENS FOR THE TREATMENT OF HAIR LOSS DISORDERS WITH DEUTERATED JAK INHIBITORS
20230322787PROCESS FOR PREPARING ENANTIOMERICALLY ENRICHED JAK INHIBITORS
1020230093504중수소화된 JAK 억제제를 이용한 탈모 장애의 치료를 위한 요법
WO/2023/018954TREATMENT OF JAK-INHIBITION-RESPONSIVE DISORDERS WITH PRODRUGS OF JAK INHIBITORS
2022171838TREATMENT OF ALOPECIA CAUSED BY DEUTERATED JAK INHIBITOR
2022171838TREATMENT OF ALOPECIA CAUSED BY DEUTERATED JAK INHIBITOR
20220226327Combination therapy comprising JAK pathway inhibitor and rock inhibitor
20220213105PROCESS FOR PREPARING ENANTIOMERICALLY ENRICHED JAK INHIBITORS
20220202834JAK inhibitor with a vitamin D analog for treatment of skin diseases
20210387991Deuterated JAK inhibitor and uses thereof SUN
WO/2020/163653PROCESS FOR PREPARING ENANTIOMERICALLY ENRICHED JAK INHIBITORS CONCERT
20200222408TREATMENT OF HAIR LOSS DISORDERS WITH DEUTERATED JAK INHIBITORS
2019516684Treatment of Hair Loss Disorders with Deuterated JAK Inhibitors
PATENT
US20210387991
USE OF COMPD NOT SYNTHESIS
https://patentscope.wipo.int/search/en/detail.jsf?docId=US344953814&_cid=P12-M0XGHQ-19840-2
Example 1
Synthesis of Compound 10
| HRMS: Agilent 6530 Q-TOF LC/MS system with electrospray ionization in positive mode. The measured time-of-flight mass-to-charge ratio (m/z) is 333.22839 (theoretical value=333.22735). |
| Clinical data | |
|---|---|
| Trade names | Leqselvi |
| Other names | CTP-543 |
| License data | US DailyMed: Deuruxolitinib |
| Routes of administration | By mouth |
| Drug class | Janus kinase inhibitor |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 1513883-39-0as phosphate: 2147706-60-1 |
| PubChem CID | 72704611as phosphate: 154572727 |
| DrugBank | DB18847 |
| ChemSpider | 115010950 |
| UNII | 0CA0VSF91Yas phosphate: 8VJ43S4LCM |
| KEGG | D11866as phosphate: D11867 |
| ChEMBL | ChEMBL4594381 |
| Chemical and physical data | |
| Formula | C17H18N6 |
| Molar mass | 306.373 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
References
King B, Mesinkovska N, Mirmirani P, Bruce S, Kempers S, Guttman-Yassky E, Roberts JL, McMichael A, Colavincenzo M, Hamilton C, Braman V, Cassella JV: Phase 2 randomized, dose-ranging trial of CTP-543, a selective Janus Kinase inhibitor, in moderate-to-severe alopecia areata. J Am Acad Dermatol. 2022 Aug;87(2):306-313. doi: 10.1016/j.jaad.2022.03.045. Epub 2022 Mar 29. [Article]Yan T, Wang T, Tang M, Liu N: Comparative efficacy and safety of JAK inhibitors in the treatment of moderate-to-severe alopecia areata: a systematic review and network meta-analysis. Front Pharmacol. 2024 Apr 10;15:1372810. doi: 10.3389/fphar.2024.1372810. eCollection 2024. [Article]Barati Sedeh F, Michaelsdottir TE, Henning MAS, Jemec GBE, Ibler KS: Comparative Efficacy and Safety of Janus Kinase Inhibitors Used in Alopecia Areata: A Systematic Review and Meta-analysis. Acta Derm Venereol. 2023 Jan 25;103:adv00855. doi: 10.2340/actadv.v103.4536. [Article]Sardana K, Bathula S, Khurana A: Which is the Ideal JAK Inhibitor for Alopecia Areata – Baricitinib, Tofacitinib, Ritlecitinib or Ifidancitinib – Revisiting the Immunomechanisms of the JAK Pathway. Indian Dermatol Online J. 2023 Jun 28;14(4):465-474. doi: 10.4103/idoj.idoj_452_22. eCollection 2023 Jul-Aug. [Article]FDA Approved Drug Products: LEQSELVI (deuruxolitinib) tablets, for oral use [Link]AJMC: FDA Approves Deuruxolitinib for Alopecia Areata [Link]
^ Jump up to:a b c d “Archived copy” (PDF). Archived (PDF) from the original on 29 July 2024. Retrieved 26 July 2024.
- ^ King, Brett; Mesinkovska, Natasha; Mirmirani, Paradi; Bruce, Suzanne; Kempers, Steve; Guttman-Yassky, Emma; et al. (August 2022). “Phase 2 randomized, dose-ranging trial of CTP-543, a selective Janus Kinase inhibitor, in moderate-to-severe alopecia areata”. Journal of the American Academy of Dermatology. 87 (2): 306–313. doi:10.1016/j.jaad.2022.03.045. ISSN 1097-6787. PMID 35364216. S2CID 247866262.
- ^ SEDEH, Farnam Barati; MICHAELSDÓTTIR, Thorunn Elísabet; HENNING, Mattias Arvid Simon; JEMEC, Gregor Borut Ernst; IBLER, Kristina Sophie (25 January 2023). “Comparative Efficacy and Safety of Janus Kinase Inhibitors Used in Alopecia Areata: A Systematic Review and Meta-analysis”. Acta Dermato-Venereologica. 103: 4536. doi:10.2340/actadv.v103.4536. ISSN 0001-5555. PMC 10391778. PMID 36695751.
- ^ “U.S. FDA Approves Leqselvi (deuruxolitinib), an Oral JAK Inhibitor for the Treatment of Severe Alopecia Areata” (Press release). Sun Pharmaceutical. 25 July 2024. Archived from the original on 26 July 2024. Retrieved 26 July 2024 – via PR Newswire.
- ^ http://www.leqselvi.com/&a=Prescribing Information
- ^ World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 86”. WHO Drug Information. 35 (3). hdl:10665/346562.
- ^ “Deuruxolitinib”. American Medical Association. Retrieved 27 July 2024.
Further reading
Passeron T, King B, Seneschal J, Steinhoff M, Jabbari A, Ohyama M, et al. (2023). “Inhibition of T-cell activity in alopecia areata: recent developments and new directions”. Frontiers in Immunology. 14: 1243556. doi:10.3389/fimmu.2023.1243556. PMC 10657858. PMID 38022501.
External links
- “Deuruxolitinib (Code C175770)”. NCI Thesaurus.
- “Deuruxolitinib Phosphate (Code C175771)”. NCI Thesaurus.
- Clinical trial number NCT04518995 for “Study to Evaluate the Efficacy and Safety of CTP-543 in Adults With Moderate to Severe Alopecia Areata (THRIVE-AA1) (THRIVE-AA1)” at ClinicalTrials.gov
- Clinical trial number NCT04797650 for “Study to Evaluate the Efficacy and Safety of CTP-543 in Adults With Moderate to Severe Alopecia Areata (THRIVE-AA2) (THRIVE-AA2)” at ClinicalTrials.gov
////Deuruxolitinib, alopecia areata, Leqselvi , approvals 2024, fda 2024, C-21543, CTP 543, CTP-543, CTP543, UNII-0CA0VSF91Y, WHO 11622
Zelatriazin
Zelatriazin,
C18H15F3N4O3, 392.3 g/mol
1929519-13-0
NBI-1065846 or TAK-041
Phase 2
(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide
Zelatriazin (NBI-1065846 or TAK-041) is a small-molecule agonist of GPR139. It was developed for schizophrenia and anhedonia in depression but trials were unsuccessful and its development was discontinued in 2023.[1][2][3][4][5][6][7]
SCHEME
SYN
WO2016081736
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016081736&_cid=P21-M0X9BK-38013-1
Example 2: (S)-2-(4-oxobenzo[d][l,2,3]triazin-3(4H)-yl)-N-(l-(4-(trifluoromethoxy)phenyl)ethyl)acetamide
[0166] To a vial containing 2-(4-oxobenzo[d][l,2,3]triazin-3(4H)-yl)acetic acid (15 mg, 0.073 mmol), HOBT (15 mg, 0.095 mmol) and EDC (21 mg, 0.110 mmol) was added DMF (244 μΕ). After stirring at RT for 5 min, (S)- 1 -(4-(trifluoromethoxy)phenyl)ethanamine (18 mg, 0.088 mmol) and DIPEA (64, 0.366 mmol) were added. The reaction mixture was
allowed to stir at RT for 1 h then water was added (5 mL). The solid was filtered off and washed with water to yield the title compound as a white solid (20 mg, 71 % yield). XH NMR
(500 MHz, DMSO-i¾) δ ppm 1.40 (d, J=6.8 Hz, 3 H), 4.98 (quin, J=7.1 Hz, 1 H), 5.09 (s, 2
H), 7.33 (d, J=7.8 Hz, 2 H), 7.44 – 7.49 (m, 2 H), 7.93 – 7.98 (m, 1 H), 8.09 – 8.15 (m, 1 H),
8.21 – 8.29 (m, 2 H), 8.85 (d, J=7.8 Hz, 1 H); ESI-MS m/z [M+H]+ 393.9.
REF
Takeda Pharmaceutical Company Limited, WO2016081736
WO2022058791
Journal of Medicinal Chemistry (2021), 64(15), 11527-11542
Publication Name: Journal of Medicinal Chemistry, Publication Date: 2023-10-13, PMID: 37830160
DOI: 10.1021/acs.jmedchem.3c01034
PATENT
https://patents.google.com/patent/US9556130B2/en
Example 2(S)-2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4-(trifluoromethoxy)phenyl)ethyl)acetamide
To a vial containing 2-(4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)acetic acid (15 mg, 0.073 mmol), HOBT (15 mg, 0.095 mmol) and EDC (21 mg, 0.110 mmol) was added DMF (244 μL). After stirring at RT for 5 min, (S)-1-(4-(trifluoromethoxy)phenyl)ethanamine (18 mg, 0.088 mmol) and DIPEA (64, 0.366 mmol) were added. The reaction mixture was allowed to stir at RT for 1 h then water was added (5 mL). The solid was filtered off and washed with water to yield the title compound as a white solid (20 mg, 71% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.40 (d, J=6.8 Hz, 3H), 4.98 (quin, J=7.1 Hz, 1H), 5.09 (s, 2H), 7.33 (d, J=7.8 Hz, 2H), 7.44-7.49 (m, 2H), 7.93-7.98 (m, 1H), 8.09-8.15 (m, 1H), 8.21-8.29 (m, 2H), 8.85 (d, J=7.8 Hz, 1H); ESI-MS m/z [M+H]+ 393.9.
PATENT
| Clinical data | |
|---|---|
| Other names | NBI-1065846; TAK-041 |
| Legal status | |
| Legal status | Investigational |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 1929519-13-0 |
| PubChem CID | 121349608 |
| Chemical and physical data | |
| Formula | C18H15F3N4O3 |
| Molar mass | 392.338 g·mol−1 |
References
- ^ Kamel, Amin; Bowlin, Steve; Hosea, Natalie; Arkilo, Dimitrios; Laurenza, Antonio (February 2021). “In Vitro Metabolism of Slowly Cleared G Protein–Coupled Receptor 139 Agonist TAK-041 Using Rat, Dog, Monkey, and Human Hepatocyte Models (HepatoPac): Correlation with In Vivo Metabolism”. Drug Metabolism and Disposition. 49 (2): 121–132. doi:10.1124/dmd.120.000246. PMID 33273044. S2CID 227282766.
- ^ Schiffer, Hans; Atienza, Josephine; Reichard, Holly; Mulligan, Victoria; Cilia, Jackie; Monenschein, Holger; Collia, Deanna; Ray, Jim; Kilpatrick, Gavin; Brice, Nicola; Carlton, Mark; Hitchcock, Steve; Corbett, Ged; Hodgson, Robert (18 May 2020). “S180. The Selective Gpr139 Agonist Tak-041 Reverses Anhedonia and Social Interaction Deficits in Rodent Models Related to Negative Symptoms in Schizophrenia”. Schizophrenia Bulletin. 46 (Supplement_1): S106–S107. doi:10.1093/schbul/sbaa031.246. PMC 7234360.
- ^ Yin, Wei; Han, David; Khudyakov, Polyna; Behrje, Rhett; Posener, Joel; Laurenza, Antonio; Arkilo, Dimitrios (August 2022). “A phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy participants and patients with stable schizophrenia”. British Journal of Clinical Pharmacology. 88 (8): 3872–3882. doi:10.1111/bcp.15305. PMC 9544063. PMID 35277995. S2CID 247407736.
- ^ Rabiner, Eugenii A.; Uz, Tolga; Mansur, Ayla; Brown, Terry; Chen, Grace; Wu, Jingtao; Atienza, Joy; Schwarz, Adam J.; Yin, Wei; Lewis, Yvonne; Searle, Graham E.; Dennison, Jeremy M. T. J.; Passchier, Jan; Gunn, Roger N.; Tauscher, Johannes (June 2022). “Endogenous dopamine release in the human brain as a pharmacodynamic biomarker: evaluation of the new GPR139 agonist TAK-041 with [11C]PHNO PET”. Neuropsychopharmacology. 47 (7): 1405–1412. doi:10.1038/s41386-021-01204-1. PMC 9117280. PMID 34675381.
- ^ Reichard, Holly A.; Schiffer, Hans H.; Monenschein, Holger; Atienza, Josephine M.; Corbett, Gerard; Skaggs, Alton W.; Collia, Deanna R.; Ray, William J.; Serrats, Jordi; Bliesath, Joshua; Kaushal, Nidhi; Lam, Betty P.; Amador-Arjona, Alejandro; Rahbaek, Lisa; McConn, Donavon J.; Mulligan, Victoria J.; Brice, Nicola; Gaskin, Philip L. R.; Cilia, Jackie; Hitchcock, Stephen (12 August 2021). “Discovery of TAK-041: a Potent and Selective GPR139 Agonist Explored for the Treatment of Negative Symptoms Associated with Schizophrenia”. Journal of Medicinal Chemistry. 64 (15): 11527–11542. doi:10.1021/acs.jmedchem.1c00820. PMID 34260228. S2CID 235908256.
- ^ Münster, Alexandra; Sommer, Susanne; Kúkeľová, Diana; Sigrist, Hannes; Koros, Eliza; Deiana, Serena; Klinder, Klaus; Baader-Pagler, Tamara; Mayer-Wrangowski, Svenja; Ferger, Boris; Bretschneider, Tom; Pryce, Christopher R.; Hauber, Wolfgang; von Heimendahl, Moritz (August 2022). “Effects of GPR139 agonism on effort expenditure for food reward in rodent models: Evidence for pro-motivational actions”. Neuropharmacology. 213: 109078. doi:10.1016/j.neuropharm.2022.109078. PMID 35561791. S2CID 248574904.
- ^ Taylor, Nick Paul (10 November 2023). “Neurocrine hit with one-two punch as Takeda and Xenon pacts deliver midphase flops”. Fierce Biotech. Retrieved 4 December 2023.
//////Zelatriazin, 1929519-13-0, NBI-1065846, TAK-041, Phase 2
Vorasidenib
Vorasidenib
6-(6-chloropyridin-2-yl)-N2,N4-bis[(2R)-1,1,1-trifluoropropan-2-yl]-1,3,5-triazine-2,4-diamine
CAS 1644545-52-7, C14H13ClF6N6, 414.74
FDA APPROVED, 8/6/2024, Voranigo, To treat Grade 2 astrocytoma or oligodendroglioma
UNII 789Q85GA8P
- AG 881
- AG-881
- AG881
| Ingredient | UNII | CAS | InChI Key |
|---|---|---|---|
| Vorasidenib citrate | X478M962XG | 2316810-02-1 | YOUTVRFNJAAFNS-DLVAHKFUSA-N |
| Vorasidenib citrate anhydrous | W4XG3EQK7B | 2316810-00-9 | OCEHQNOYRLHJCI-WPRTUUMNSA-N |
Vorasidenib, sold under the brand name Voranigo, is an anti-cancer medication used for the treatment of certain forms of glioma.[1][2] Vorasidenib acts to inhibit the enzymes isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2).[1][2]
The most common adverse reactions include fatigue, headache, increased risk of COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizures.[2]
Vorasidenib was approved for medical use in the United States in August 2024.[2][3] It is the first approval by the US Food and Drug Administration (FDA) of a systemic therapy for people with grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation.[2]
Medical uses
Vorasidenib is indicated for the treatment of people aged twelve years of age and older with grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation, following surgery including biopsy, sub-total resection, or gross total resection.[2]
Side effects
The most common adverse reactions include fatigue, headache, increased risk of COVID-19 infection, musculoskeletal pain, diarrhea, nausea, and seizures.[2] The most common grade 3 or 4 laboratory abnormalities include increased alanine aminotransferase, increased aspartate aminotransferase, GGT increased, and decreased neutrophils.[2]
History
Efficacy was evaluated in 331 participants with grade 2 astrocytoma or oligodendroglioma with a susceptible isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation following surgery enrolled in INDIGO (NCT04164901), a randomized, multicenter, double-blind, placebo-controlled trial.[2] Participants were randomized 1:1 to receive vorasidenib 40 mg orally once daily or placebo orally once daily until disease progression or unacceptable toxicity.[2] Isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 mutation status was prospectively determined by the Life Technologies Corporation Oncomine Dx Target Test.[2] Participants randomized to placebo were allowed to cross over to vorasidenib after documented radiographic disease progression.[2] Participants who received prior anti-cancer treatment, including chemotherapy or radiation therapy, were excluded.[2]
Society and culture
Legal status
Vorasidenib was approved for medical use in the United States in August 2024.[2]
The FDA granted the application for vorasidenib priority review, fast track, breakthrough therapy, and orphan drug designations.[2]
SYN
WO/2024/161041NOVEL COMPOUNDS THAT CAN BE USED AS THERAPEUTIC AGENTS
20240254118PRMT5 INHIBITORS AND USES THEREOF
118359585共晶体、其药物组合物以及涉及其的治疗方法
WO/2024/148437USE OF PCLX-001 OR PCLX-002 AS A RADIOSENSITIZER
20240238424HETEROBIFUNCTIONAL COMPOUNDS AND METHODS OF TREATING DISEASE
1020240097895CD73 화합물
WO/2024/137852PRMT5 INHIBITORS AND USES THEREOF
2024057088THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
20240116928CD73 COMPOUNDS
117586228Preparation method of triazine medicine
20240041892THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
117529323Therapeutically active compounds and methods of use thereof
WO/2024/006929CD73 COMPOUNDS
PATENT
https://patents.google.com/patent/US10028961B2/en
Step 3: Preparation of 6-(6-chloropyridin-2-yl)-N2,N4-bis((R)-1,1,1-trifluoro propan-2-yl)-1,3,5-triazine-2,4-diamine
A mixture of 2,4-dichloro-6-(6-chloro-pyridin-2-yl)-1,3,5-triazine (0.27 g, 1.04 mol), (R)-1,1,1-trifluoropropan-2-amine hydrochloride (0.39 g, 2.6 mol), and potassium carbonate (0.43 g, 3.1 mol) in dry 1,4-dioxane (2.5 mL) was stirred under the atmosphere of N2 at 50° C. for 36 hr then at 100° C. for another 36 hr until the reaction was complete. The resulting mixture was filtered through Celite and the cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by standard methods to give the desired product.
1H NMR (400 MHz, CDCl3) δ 8.32 (m, 1H), 7.80 (m, 1H), 7.48 (d, J=7.9 Hz, 1H), 5.61 (m, 1.5H), 5.25 (m, 0.5H), 5.09 (m, 0.5H), 4.88 (m, 1.5H), 1.54-1.26 (m, 6H). LC-MS: m/z 415 (M+H)+.
The procedure set forth in Example 10 was used to produce the following compounds using the appropriate starting materials.Compound 6-(6-Chloropyridin-2-yl)-N2,N4-bis((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine
1H NMR (400 MHz, CDCl3) δ 8.29-8.16 (m, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 5.70-5.13 (m, 2H), 5.09-4.71 (m, 2H), 1.34 (m, 6H). LC-MS: m/z 415 (M+H)+.Compound 6-(6-Chloropyridin-2-yl)-N2—((R)-1,1,1-trifluoropropan-2-yl)-N4—((S)-1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine
1H NMR (400 MHz, CDCl3) δ 8.41-8.23 (m, 1H), 7.83 (s, 1H), 7.51 (d, J=6.2 Hz, 1H), 5.68-5.20 (m, 2H), 5.18-4.81 (m, 2H), 1.48-1.39 (m, 6H). LC-MS: m/z 415 (M+H)+.Compound 6-(6-Chloropyridin-2-yl)-N2,N4-bis(1,1,1-trifluoropropan-2-yl)-1,3,5-triazine-2,4-diamine
1H NMR (400 MHz, CDCl3) δ 8.29-8.16 (m, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 5.70-5.13 (m, 2H), 5.09-4.71 (m, 2H), 1.34 (m, 6H). LC-MS: m/z 415 (M+H)+.
| Clinical data | |
|---|---|
| Trade names | Voranigo |
| License data | US DailyMed: Vorasidenib |
| Routes of administration | By mouth |
| ATC code | None |
| Legal status | |
| Legal status | US: ℞-only[1] |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 1644545-52-7 |
| PubChem CID | 117817422 |
| IUPHAR/BPS | 10663 |
| DrugBank | DB17097 |
| ChemSpider | 64835242 |
| UNII | 789Q85GA8P |
| KEGG | D11834 |
| ChEMBL | ChEMBL4279047 |
| Chemical and physical data | |
| Formula | C14H13ClF6N6 |
| Molar mass | 414.74 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
References
^ Jump up to:a b c “Voranigo- vorasidenib citrate tablet, film coated”. DailyMed. 9 August 2024. Retrieved 15 August 2024.
- ^ Jump up to:a b c d e f g h i j k l m n o “FDA approves vorasidenib for Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation”. U.S. Food and Drug Administration (FDA). 6 August 2024. Archived from the original on 7 August 2024. Retrieved 7 August 2024.
This article incorporates text from this source, which is in the public domain. - ^ “Servier’s Voranigo (vorasidenib) Tablets Receives FDA Approval as First Targeted Therapy for Grade 2 IDH-mutant Glioma” (Press release). Servier Pharmaceuticals. 6 August 2024. Archived from the original on 7 August 2024. Retrieved 7 August 2024 – via PR Newswire.
Further reading
- Mellinghoff IK, Lu M, Wen PY, Taylor JW, Maher EA, Arrillaga-Romany I, et al. (March 2023). “Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial”. Nature Medicine. 29 (3): 615–622. doi:10.1038/s41591-022-02141-2. PMC 10313524. PMID 36823302.
- Mellinghoff IK, Penas-Prado M, Peters KB, Burris HA, Maher EA, Janku F, et al. (August 2021). “Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I Trial”. Clinical Cancer Research : An Official Journal of the American Association for Cancer Research. 27 (16): 4491–4499. doi:10.1158/1078-0432.CCR-21-0611. PMC 8364866. PMID 34078652.
- Mellinghoff IK, van den Bent MJ, Blumenthal DT, Touat M, Peters KB, Clarke J, et al. (August 2023). “Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma”. The New England Journal of Medicine. 389 (7): 589–601. doi:10.1056/NEJMoa2304194. PMID 37272516.
- Popovici-Muller J, Lemieux RM, Artin E, Saunders JO, Salituro FG, Travins J, et al. (April 2018). “Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers”. ACS Medicinal Chemistry Letters. 9 (4): 300–305. doi:10.1021/acsmedchemlett.7b00421. PMC 5900343. PMID 29670690.
External links
Clinical trial number NCT04164901 for “Study of Vorasidenib (AG-881) in Participants With Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation (INDIGO)” at ClinicalTrials.gov
- Clinical trial number NCT02481154 for “Study of Orally Administered AG-881 in Patients With Advanced Solid Tumors, Including Gliomas, With an IDH1 and/or IDH2 Mutation” at ClinicalTrials.gov
- Clinical trial number NCT03343197 for “Study of AG-120 and AG-881 in Subjects With Low Grade Glioma” at ClinicalTrials.gov
////////Vorasidenib, Voranigo, FDA 2024, APPROVALS 2024, AG 881, AG-881, AG881
Arbemnifosbuvir, AT-752, PD160572
Arbemnifosbuvir, AT-752, 1998705-63-7, PD160572
E9V7VHK36U INN 12706
C24H33FN7O7P 581.5 g/mol
SYN
propan-2-yl (2S)-2-[[[(2R,3R,4R,5R)-5-[2-amino-6-(methylamino)purin-9-yl]-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate
L-ALANINE, N-((P(R),2’R)-2-AMINO-2′-DEOXY-2′-FLUORO-N,2′-DIMETHYL-P-PHENYL-5′ -ADENYLYL)-, 1-METHYLETHYL ESTER
N-((P(R),2’R)-2-AMINO-2′-DEOXY-2′-FLUORO-N,2′-DIMETHYL-P-PHENYL-5′ -ADENYLYL)-L-ALANINE 1-METHYLETHYL ESTER
WO2022040473 Atea Pharmaceuticals, Inc.
CN113784721
US20160257706
WO2022076903 US10874687
PATENT
US20160257706
https://patentscope.wipo.int/search/en/detail.jsf?docId=US177601863&_cid=P11-M0VTE4-38538-1
Example 1. Preparation of isopropyl ((((R,S)-(2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-phenoxy-phosphoryl)-L-alaninate
Step 1. Preparation of ((2R,3R,4R,5R)-3-(benzoyloxy)-5-bromo-4-fluoro-4-methyltetrahydrofuran-2-yl)methyl benzoate (2)
Step 2. Preparation of (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate (3)
Step 3. Preparation of (2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-ol (4)
Step 4. Preparation of isopropyl ((((R,S)-(2R,3R,4R,5R)-5-(2-amino-6-(methylamino)-9H-purin-9-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)-phenoxy-phosphoryl)-L-alaninate (5)
PATENT
/////Arbemnifosbuvir, AT-752, 1998705-63-7, PD160572, E9V7VHK36U INN 12706
Zelicapavir
Zelicapavir, Enanta Pharmaceuticals
Alternative Names: EDP-938; EP 023938
cas 2070852-76-3
RSV-IN-7
549.5 g/mol, C27H22F3N7O3
UNII U4OI721DMD
(3S)-3-[[5-[3-morpholin-4-yl-5-(trifluoromethyl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl]amino]-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one
SYN
New England Journal of Medicine (2022), 386(7), 655-666
WO2022157327
WO2018152413
WO2019067864
WO2017015449
PATENT
WO2018152413
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018152413&_cid=P20-M0V26A-30323-1
Step 5 : (<Sf)-3-((5-(3-morpholino-5-(trifluoromethyl)pyridin-2-yl)-1.3.4-oxadiazol-2-
To a mixture of (5)-2-(3-morpholino-5-(trifluoromethyl)picolinoyl)-N-2-oxo-5-phenyl-2,3-dihydro-lH-benzo[e] [l,4]diazepin-3-yl)hydrazine-l-carboxamide (1.4 kg, 1 eq.) in DCM (11.2 L) in a flask was charged with 4A-MS (1.4 kg) and stirred at 20±5 °C for 2hrs. Then, it was cooled to 0°C, charged with triethylamine (0.62 Kg, 2.5 eq.) and stirred for 10 min. /^-Toluenesulfonyl chloride (0.7 kg, 1.5 eq.) in DCM (1.4 L) solution was dropwise added to the reaction mixture with maintaining below 5°C and stirred at at 0±5 °C for 5 hrs. The reaction mixture was filtered and washed with DCM (2 X 4.2 L). The filtrate was treated with water (4.2 L) at 0°C and stirred between 0 and 10°C for 5 min. After separation, the organic phase was washed with 5% aqueous NaHCC solution (7 L), water (7 L) and brine (7 L) successively and separated. The DCM layer was concentrated in vacuo at below 30°C to leave ~7L of organic layer. MTBE (7 L) was added to organic layer and concentrated in vacuo to leave ~ 7 L of organic layer (This step was repeated once). The organic layer was charged with water (7 L) and stirred at 20±5 °C for 4 hrs. The solid was filtered and washed with MTBE (3 X 2.1 L) and purified water (2.8 L). The wet cake was stirred with ethyl acetate (7 L) for 12 hrs, charged with n-heptane (14 L) and stirred at 20±5 °C for 5 hrs. The solid was filtered, washed with n-heptane (2 X 2.8 L) and dried under vacuum at ambient temperature to provide the title compound (0.776 kg, 99.6% purity by HPLC, 97.8%
chiral purity by chiral HPLC) as a pale yellowish solid. LC-MS(ESI, m/z): 550.17 [M+H]+;
¾ NMR: ( DMSO-c 6400 MHz): δ 10.98 (br-s, 1H), 9.40 (d, J=8.0 Hz, 1H), 8.69 (br-d, J=4.0 Hz, 1H), 7.89 (d, J=4.0 Hz, 1H), 7.68 (dt, J=8.0 and 4.0 Hz, 1H), 7.56-7.51 (m, 3H), 7.49-7.45 (m, 2H), 7.38-7.35 (m, 2H), 7.29 (br-t, J=8.0 Hz, 1H)
5.22 (d, J=8.0 Hz, 1H), 3.75-3.72 (m, 4H), 3.09-3.07 (m, 4H); 13C (DMSO-c¾, 100 MHz): δ 167.3, 167.0, 162.8, 156.4, 147.2, 139.2, 138.7, 138.4, 138.3, 138.0, 132.30, 130.7, 130.5, 129.5, 128.4, 126.2, 124.5, 123.4, 121.5, 71.8, 65.9, 51.0.
SCHEME
PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=US368999603&_cid=P20-M0V2BF-36596-1
Example 253
Example 160 was prepared using a procedure similar to that used to prepare Example 152 where methyl 5-cyano-3-morpholinopicolinate was used in place of ethyl 2-morpholino-4-(trifluoromethyl)benzoate. ESI-MS m/z: 507.2 [M+H] +. 1H NMR (400 MHz, DMSO-d 6) δ 3.02-3.04 (m, 4H), 3.71-3.73 (m, 4H), 5.19-5.21 (d, J=8.0 Hz, 1H), 7.26-7.30 (m, 1H), 7.34-7.36 (m, 2H), 7.44-7.55 (m, 5H), 7.65-7.70 (m, 1H), 8.13 (s, 1H), 8.72 (s, 1H), 9.42-9.45 (m, 1H), 10.98 (s, 1H).
//////////////Zelicapavir, EDP-938, EP 023938, EDP 938, RSV-IN-7, ENANTA
Palopegteriparatide
Palopegteriparatide
Yorvipath , FDA 2024, 8/9/2024, To treat hypoparathyroidism
- G2N64C3385
- 2222514-07-8
- Palopegteriparatide
- UNII-G2N64C3385
- ACP-014
- Mpeg 40000-teriparatide
- Palopegteriparatide [INN]
- Transcon parathyroid hormone (1-34)
- Transcon pth (1-34)
- Palopegteriparatide [USAN]
- TransCon PTH
- WHO 11060
Palopegteriparatide, sold under the brand name Yorvipath, is a hormone replacement therapy used for the treatment of hypoparathyroidism.[1][2] It is a transiently pegylated parathyroid hormone.[4] It is a parathyroid hormone analog.[1]
Palopegteriparatide was approved for medical use in the European Union in November 2023,[2] and in the United States in August 2024.[1][5]
Medical uses
Palopegteriparatide is indicated for the treatment of adults with hypoparathyroidism.[1][2]
Adverse effects
The US Food and Drug Administration (FDA) prescription label for palopegteriparatide includes warnings for a potential risk of risk of unintended changes in serum calcium levels related to number of daily injections and total delivered dose, serious hypocalcemia and hypercalcemia (blood calcium levels that are too high), osteosarcoma (a rare bone cancer) based on findings in rats, orthostatic hypotension (dizziness when standing), and a risk of a drug interaction with digoxin (a medicine for certain heart conditions).[5]
History
The effectiveness of palopegteriparatide was evaluated in a 26-week, randomized, double-blind, placebo-controlled trial that enrolled 82 adults with hypoparathyroidism.[5] Prior to randomization, all participants underwent an approximate four-week screening period in which calcium and active vitamin D supplements were adjusted to achieve an albumin-corrected serum calcium concentration between 7.8 and 10.6 mg/dL, a magnesium concentration ≥1.3 mg/dL and below the upper limit of the reference range, and a 25(OH) vitamin D concentration between 20 to 80 ng/mL.[5] During the double-blind period, participants were randomized to either palopegteriparatide (N = 61) or placebo (N= 21), at a starting dose of 18 mcg/day, co-administered with conventional therapy (calcium and active vitamin D).[5] Study drug and conventional therapy were subsequently adjusted according to the albumin-corrected serum calcium levels.[5] At the end of the trial, 69% of the participants in the palopegteriparatide group compared to 5% of the participants in the placebo group were able to maintain their calcium level in the normal range, without needing active vitamin D and high doses of calcium (calcium dose ≤ 600 mg/day).[5]
The FDA granted the application for palopegteriparatide orphan drug and priority review designations.[5]
Society and culture
Legal status
In September 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Yorvipath, intended for the treatment of chronic hypoparathyroidism in adults.[4][6] The applicant for this medicinal product is Ascendis Pharma Bone Diseases A/S.[4] Palopegteriparatide was approved for medical use in the European Union in November 2023.[2]
Palopegteriparatide was granted an orphan drug designation by the US Food and Drug Administration (FDA) in 2018,[7] and by the EMA in 2020.[8]
Brand names
Palopegteriparatide is the international nonproprietary name.[9][10]
Palopegteriparatide is sold under the brand name Yorvipath.[2]
References
- ^ Jump up to:a b c d e “Yorvipath injection, solution”. DailyMed. 14 August 2024. Retrieved 5 September 2024.
- ^ Jump up to:a b c d e f “Yorvipath EPAR”. European Medicines Agency. 19 October 2020. Archived from the original on 10 December 2023. Retrieved 11 December 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ “Yorvipath Product information”. Union Register of medicinal products. 20 November 2023. Archived from the original on 26 November 2023. Retrieved 11 December 2023.
- ^ Jump up to:a b c “Yorvipath: Pending EC decision”. European Medicines Agency. 15 September 2023. Archived from the original on 24 September 2023. Retrieved 24 September 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ Jump up to:a b c d e f g h “FDA approves new drug for hypoparathyroidism, a rare disorder”. U.S. Food and Drug Administration (FDA) (Press release). 9 August 2024. Archived from the original on 13 August 2024. Retrieved 13 August 2024. This article incorporates text from this source, which is in the public domain.
- ^ “Ascendis Pharma Receives Positive CHMP Opinion for TransCon PTH (palopegteriparatide) for Adults with Chronic Hypoparathyroidism”. Ascendis Pharma (Press release). 14 September 2023. Archived from the original on 24 September 2023. Retrieved 24 September 2023.
- ^ “TransCon Parathyroid Hormone (mPEG conjugated parathyroid hormone 1-34) Orphan Drug Designations and Approvals”. U.S. Food and Drug Administration (FDA). Archived from the original on 24 September 2023. Retrieved 24 September 2023.
- ^ “EU/3/20/2350”. European Medicines Agency. 15 September 2023. Archived from the original on 24 September 2023. Retrieved 24 September 2023.
- ^ World Health Organization (2021). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 86”. WHO Drug Information. 35 (3). hdl:10665/346562.
- ^ World Health Organization (2023). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 89”. WHO Drug Information. 37 (1). hdl:10665/366661.
External links
- Palopegteriparatide Global Substance Registration System
- Palopegteriparatide NCI Thesaurus
- Clinical trial number NCT04701203 for “A Trial Investigating the Safety, Tolerability and Efficacy of TransCon PTH Administered Daily in Adults With Hypoparathyroidism (PaTHway)” at ClinicalTrials.gov
| Clinical data | |
|---|---|
| Trade names | Yorvipath |
| Other names | ACP-014, TransCon PTH |
| License data | US DailyMed: Palopegteriparatide |
| Routes of administration | Subcutaneous |
| Drug class | Hormonal agent |
| ATC code | H05AA05 (WHO) |
| Legal status | |
| Legal status | US: ℞-only[1]EU: Rx-only[2][3] |
| Identifiers | |
| CAS Number | 2222514-07-8 |
| UNII | G2N64C3385 |
| KEGG | D12395 |
//////Palopegteriparatide, APPRoVALS 2024, FDA 2024, Yorvipath, hypoparathyroidism, UNII-G2N64C3385, ACP-014, TransCon PTH, WHO 11060
Aneratrigine
Aneratrigine
2097163-74-9
5-chloro-2-fluoro-4-[4-fluoro-2-[methyl-[2-(methylamino)ethyl]amino]anilino]-N-(1,3-thiazol-4-yl)benzenesulfonamide
5-chloro-2-fluoro-4-((4-fluoro-2-(3-(methylamino)pyridin-1-yl)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide hydrochloride
| Benzenesulfonamide, 5-chloro-2-fluoro-4-[[4-fluoro-2-[methyl[2-(methylamino)ethyl]amino]phenyl]amino]-N-4-thiazolyl- |
C19H20ClF2N5O2S2 488.0 g/mol
UNII 6A5ZY5LT78
WHO
SYN
Assignee: Daewoong Pharmaceutical Co., Ltd.
World Intellectual Property Organization, WO2017082688
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017082688&_cid=P11-M0UEPF-95506-1
Preparation of 5-chloro-2-fluoro-4-((4-fluoro-2-(3-(methylamino)pyridin-1-yl)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide hydrochloride
Step 1) Preparation of tert-butyl (1-(2-amino-5-fluorophenyl)pyridin-3-yl)(methyl)carbamate
2,4-Difluoro-1-nitrobenzene (2.0 g, 12.6 ng/mol) and tert-butyl methyl (pyridin-3-yl)carbamate (2.5 g, 1.0 eq.) were dissolved in DMF (20 mL), and K2C03 ( 2.6 g , 1.5 eq .) was added. The internal temperature was maintained at 60–70 ° C and the mixture was stirred for 2 hours. The completion of the reaction was confirmed by TLC when the reaction solution turned deep yellow. After cooling to room temperature, ethyl acetate (EA)/H20 was added, stirred, and the layers were separated. MgS04 was added to the separated organic layer, stirred, dried, and filtered. After concentrating the filtrate under reduced pressure, the residue was dissolved in EtOH (10 mL) and distilled water (10 mL), and then Na 2 S 2 0 4 (13.0 g, 6 eq.) was added. After stirring for 2 hours while maintaining the internal temperature at 60 to 70 ° C, the completion of the reaction was confirmed by TLC when the yellow color of the reaction solution lightened and became almost colorless. After cooling to room temperature, distilled water (50 mL) was added and extracted twice with EA (100 mL). MgS0 4 was added to the organic layer, stirred, dried, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was separated by column chromatography (n-Hexane/EA = 3/1) to obtain the title compound (2.0 g, 51. ).
1H NMR (MeOD): 6.73(m, 1H), 6.57(t, 1H), 3.23(m, 1H), 3.10(m, 2H), 2.94(m, 1H), 2.91(s, 3H), 2.25( m, 1H)， 1.99(m, 1H)
Step 2) Preparation of tert-butyl thiazol-4-ylcarbamate
Thiazole-4-carboxylic acid (5.0 g, 38.8 vol) was dissolved in t-Bu0H (100 mL), and then TEA (8.1 mL, 1.5 eq.) and DPPA (7.1 mL, 1.5 eq.) were added. The internal temperature was maintained at 90–100 ° C, and the mixture was stirred for 3 days. The completion of the reaction was confirmed by TLC. The product was concentrated under reduced pressure, distilled water (50 mL) was added, and the solution was washed with EA (100 mL).
It was extracted twice. MgSQ 4 was added to the organic layer, stirred, dried, and filtered.
After concentrating the filtrate under reduced pressure, the residue was added to a small amount of EA, slurried, and the resulting solid was filtered to obtain the white title compound (4.0 g, 51.5%).
1H NMR (MeOD): 8.73(s, 1H), 7.24(s, 1H), 1.52(s, 9H)
Step 3) Preparation of tert-butyl ((4-bromo-5-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate
Step 2) The tert-Butyl thiazol-4-ylcarbamate (4.0 g, 20.0 ng ol) prepared in the reaction vessel was placed in a reaction vessel and the interior was replaced with nitrogen gas. After dissolving in THF (32 mL), it was cooled to _78 ° C using dry ice— acetone. After cooling, LiHMDS (22.4 mL, 1.5 eq.) was slowly added and the reaction mass was stirred for 30 minutes. 4-Bromo-5-chloro-2-fluorobenzenesulfonyl chloride (6.0 g, 1.0 eq.) was dissolved in THF (10 mL) and slowly added to the reaction mixture. The reaction mass was stirred overnight and the completion of the reaction was confirmed by TLC. Distilled water (50 mL) was added and extracted twice with EA (100 mL). MgS0 4 was added to the organic layer, stirred, dried, and filtered. After concentrating the filtrate under reduced pressure, the residue was crystallized from THF/n-hexane to obtain the title compound (4.4 g, 59.0%).
1H NMR (MeOD): 9.00(s, 1H), 8.22(d, 1H), 7.90(d, 1H), 7.78(s, 1H), 1.35(s, 9H)
Step 4) Preparation of tert-butyl (l-(2-((4-(N-(tert-butyloxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)-2-chloro-5-fluorophenyl)amino)-5-fluorophenyl)pyrlidin-3-yl)(methyl)carbamate
Tert-butyl (1-(2-amino-5-fluorophenyl)pyrlidin-3-yl)(methyl)carbamate (0.5 g, 1.1 ng ol) prepared in Step 1) and tert-butyl ((4-bromo-5-chloro-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate (0.9 g, 1.2 eq.) prepared in Step 3) were dissolved in 1,4-dioxane (10 mL). Pd(OAc) 2 (0.03 g, 0.1 eq), rac-BINAP (0.19 g, 0.2 eq.), Cs 2 C0 3 (1.5 g, 3.0 eq.) were added to the reaction solution. After reacting at 120 ° C for 30 minutes using a microwave initiator, the completion of the reaction was confirmed by TLC. Distilled water (50 mL) was added and extracted twice with EA (100 mL).
MgS0 4 was added to the organic layer, stirred, filtered and dried. The filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (EA/n-Hexane = 1/1). This was repeated twice to obtain the title compound (2.0 g, 88.2%).
1H NMR (MeOD): 8.95(s, 1H), 7.94(d, 1H), 7.65(s, 1H), 7.14(t, 1H), 6.70(d, 1H), 6.64(t, 1H), 6.07( d, 1H)ᅳ 3.40(m, 1H), 3.28(m, 2H), 3.16(m, 1H), 2.64(s, 3H), 2.06(m, 1H), 1.89(m, 1H), 1.41(s , 9H), 1.36(s, 9H)
Step 5) Preparation of 5-chloro-2-fluoro-4-((4-fluoro-2-(3-(methylamino)pyridin-1-yl)phenyl)amino)-N-(thiazol-4-yl)benzenesulfonamide hydrochloride
Step 4) was prepared by adding 1.25 M HCl in MeOH (15 mL) to tert-butyl (1-(2-((4-(Ν-(tert-butoxycarbonyl)-N-(thiazol-4-yl)sulfamoyl)—2-chloro-5-fluorophenyl)amino)-5-fluorophenyl)pyrlidin-3-yl) (methyl)carbamate (2.0 g, 2.9 µl). The mixture was heated to 40–50 ° C and stirred overnight, and the completion of the reaction was confirmed by TLC. The product was concentrated, and methylene chloride (15 mL) was added to the residue, which was stirred for 1 hour, and the resulting solid was filtered to obtain the title compound (0.9 g, 58.8%).
1H 證 (MeOD): 8.73(s, 1H), 7.75(d, 1H), 7.12(t, 1H), 7.00(s, 1H), 6.69(d, 1H), 6.67(t, 1H), 6.05( d, 1H), 3.73(m, 1H) , 3.54(m, 1H), 3.45(m, 1H), 3.38(m, 1H), 3.26(m, 1H), 2.63(s, 3H) , 2.31(m , 1H), 1.96(m, 1H)
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////////////Aneratrigine, DAEWOONG
New Drug Approvals 
