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Iscartrelvir
Iscartrelvir
CAS 2921711-74-0
MF 2921711-74-0, 526.4 g/mol
N-{(1S,2R)-2-[4-bromo-2-(methylcarbamoyl)-6-nitroanilino]cyclohexyl}isoquinoline-4-carboxamide
antiviral, WU-04, WU 04, W2LTV65R5E
Iscartrelvir is an investigational new drug developed by the Westlake University for the treatment of COVID-19. It targets the SARS-CoV-2 3CL protease, which is crucial for the replication of the virus responsible for COVID-19.[1][2]
Iscartrelvir is a small molecule drug. The usage of the INN stem ‘-trelvir’ in the name indicates that Iscartrelvir is a antiviral 3CL protease inhibitor. Iscartrelvir has a monoisotopic molecular weight of 525.1 Da.
PAT
WO2022150962A1
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022150962&_cid=P11-MJKTXT-76321-1
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=CN331401594&_cid=P11-MJKTO7-65334-1
PAT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2024243841&_cid=P11-MJKTO7-65334-1
N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)isoquinoline-4-carboxamide, and its structure is as follows:
Example 1: Preparation of Compound 1
[0189]A free, amorphous compound 1, a yellow solid, was prepared according to the method disclosed in paragraphs [00121]-[00128] of WO2022150962A1, and was used in the following examples. The specific synthetic steps are shown in steps a to d:
The reagents and conditions for steps a to d are further described below: (a) 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIPEA), CH₂Cl₂
or
dichloromethane (DCM), 0°C, 2 h; (b) DIPEA, dimethylformamide (DMF), 80°C, 16 h; (c) 3M ethyl hydrochloride (HCl·EA), CH₂Cl₂ , 1
h ; (d ) HATU, DIPEA, DMF, room temperature, 12 h.
[0191]Step a: Synthesis of N-methyl-5-bromo-2-fluoro-3-nitrobenzamide (I-1)
[0192]A solution of 5-bromo-2-fluoro-3-nitrobenzoic acid (0.8 g, 3.80 mmol) in dichloromethane (20 mL) was stirred at 0 °C. Then, HATU (2.0 g, 5.25 mmol), DIPEA (1.88 mL, 11.4 mmol), and methylamine hydrochloride (0.31 g, 4.5 mmol) were added to the reaction mixture. The mixture was stirred at 0 °C for 2 hours until it became clear. The mixture was extracted three times with dichloromethane, and the combined organic layers were washed with a saturated brine solution. The organic phase was then dried over anhydrous Na₂SO₄ and concentrated
under vacuum. Finally, the mixture was purified by chromatography to give compound I-1 (0.8 g, 76% yield) as a yellow solid.
[0193]Step b: Synthesis of tert-butyl 2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)carbamate (I-2)
[0194]A solution of compound I-1 (0.8 g, 2.9 mmol) in 15 mL of DMF was stirred at room temperature. Then, tert-butyl ((1S,2R)-2-aminocyclohexyl)carbamate (0.75 g, 3.5 mmol) (the corresponding stereoisomer of this reagent can be used to synthesize the stereoisomer of compound I-2) and DIPEA (1.44 mL, 8.7 mmol) were added to the reaction mixture. The mixture was heated to 80 °C and stirred for 16 hours. The mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated salt solution. The organic phase was then dried over anhydrous Na₂SO₄ and concentrated under vacuum to give compound
I -2 as a yellow solid, requiring no further purification.
Step c: Synthesis of 2-(2-aminocyclohexyl)amino)-5-bromo-N-methyl-3-nitrobenzamide hydrochloride (I-3)
[0196]A solution of compound I-2 (90 mg, 0.19 mmol) (or the corresponding stereoisomer) in anhydrous dichloromethane (6 mL) was stirred at room temperature. Then, HCl (4 mL, 3 M in ethyl acetate) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum to give compound I-3 as a yellow solid, requiring no further purification.
[0197]Step d: Synthesis of N-((1S,2R)-2-((4-bromo-2-(methylcarbamoyl)-6-nitrophenyl)amino)cyclohexyl)isoquinoline-4-carboxamide
[0198]At room temperature, a solution of the corresponding isoquinoline-4-carboxylic acid (1 equivalent) and HATU (1.5 equivalent) in anhydrous DMF (6 mL) was stirred. Then, compound I-3 and DIPEA (5.0 equivalent) were added. The mixture was stirred overnight at room temperature. The mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated brine. The organic phase was then dried over anhydrous Na₂SO₄ and
concentrated under vacuum. Finally, the mixture was purified by chromatography to give compound 1 as a free amorphous solid in yellow form.
PAT
- Aromatic ring-containing pyridone amide compoundsPublication Number: CN-119100980-APriority Date: 2023-06-07
- Crystal of viral protease inhibitor and usePublication Number: WO-2024243841-A1Priority Date: 2023-05-31
- Protease inhibitors, their preparation and usePublication Number: CN-113072497-BPriority Date: 2021-01-12Grant Date: 2023-04-14
- Protease inhibitors, their preparation and usePublication Number: CN-113072497-APriority Date: 2021-01-12
- Protease inhibitors, their preparation and usePublication Number: CN-116751164-APriority Date: 2021-01-12
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……
| Clinical data | |
|---|---|
| Other names | WPV01; WU-04 |
| Identifiers | |
| IUPAC name | |
| CAS Number | 2921711-74-0 |
| PubChem CID | 156774920 |
| ChemSpider | 129307041 |
| UNII | W2LTV65R5E |
| PDB ligand | J7R (PDBe, RCSB PDB) |
| Chemical and physical data | |
| Formula | C24H24BrN5O4 |
| Molar mass | 526.391 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
References
- Yang L, Wang Z (September 2023). “Bench-to-bedside: Innovation of small molecule anti-SARS-CoV-2 drugs in China”. European Journal of Medicinal Chemistry. 257 115503. doi:10.1016/j.ejmech.2023.115503. PMC 10193775. PMID 37229831.
- Hou N, Shuai L, Zhang L, Xie X, Tang K, Zhu Y, et al. (February 2023). “Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLpro”. ACS Central Science. 9 (2): 217–227. doi:10.1021/acscentsci.2c01359. PMC 9885526. PMID 36844503.
- Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04Publication Name: Cell DiscoveryPublication Date: 2024-04-09PMCID: PMC11003996PMID: 38594245DOI: 10.1038/s41421-024-00673-0
- Identification of Ebselen derivatives as novel SARS-CoV-2 main protease inhibitors: Design, synthesis, biological evaluation, and structure-activity relationships explorationPublication Name: Bioorganic & Medicinal ChemistryPublication Date: 2023-12-15PMID: 37972434DOI: 10.1016/j.bmc.2023.117531
- The molecular mechanism of non-covalent inhibitor WU-04 targeting SARS-CoV-2 3CLpro and computational evaluation of its effectiveness against mainstream coronavirusesPublication Name: Physical chemistry chemical physics : PCCPPublication Date: 2023-09-13PMID: 37655706DOI: 10.1039/d3cp03828a
- Bench-to-bedside: Innovation of small molecule anti-SARS-CoV-2 drugs in ChinaPublication Name: European Journal of Medicinal ChemistryPublication Date: 2023-09-05PMCID: PMC10193775PMID: 37229831DOI: 10.1016/j.ejmech.2023.115503
- Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLproPublication Name: ACS Central SciencePublication Date: 2023-01-25PMCID: PMC9885526PMID: 36844503DOI: 10.1021/acscentsci.2c01359
////////iscartrelvir, antiviral, WU-04, WU 04, W2LTV65R5E
Zoracopan
Zoracopan
CAS 2243483-63-6
MF C31H31BrN6O3 MW 615.52
2-Azabicyclo[3.1.0]hexane-3-carboxamide, 2-[2-[3-acetyl-7-methyl-5-(2-methyl-5-pyrimidinyl)-1H-indol-1-yl]acetyl]-N-(6-bromo-3-methyl-2-pyridinyl)-5-methyl-, (1R,3S,5R)-
(1R,3S,5R)-2-{[3-acetyl-7-methyl-5-(2-methylpyrimidin5-yl)-1H-indol-1-yl]acetyl}-N-(6-bromo-3-methylpyridin2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamide
complement factor D inhibitor, ALXN-2080, ALXN 2080, E7799Y8LXY
Zoracopan is a selective complement factor D (CFD) inhibitor. When administered systemically (orally or intravenously), Zoracopan accumulates and is sustained-released in ocular tissues, primarily in the choroid-retinal pigment epithelium (C-RPE) and/or iridociliary body (I-CB).
Zoracopan is a small molecule drug. The usage of the INN stem ‘-copan’ in the name indicates that Zoracopan is a complement receptor antagonist/complement inhibitor. Zoracopan is under investigation in clinical trial NCT06173596 (A Study to Evaluate Potential Drug Interactions Between ALXN2080 and Itraconazole, Fluconazole & Carbamazepine in Healthy Adults). Zoracopan has a monoisotopic molecular weight of 614.16 Da.
- Safety and Tolerability, PK, and PD Study of Single and Multiple ALXN2080 Doses in Healthy ParticipantsCTID: NCT05428696Phase: Phase 1Status: CompletedDate: 2024-06-07
- A Study to Evaluate Potential Drug Interactions Between ALXN2080 and Itraconazole, Fluconazole & Carbamazepine in Healthy AdultsCTID: NCT06173596Phase: Phase 1Status: CompletedDate: 2024-06-20
- A Study to Investigate the Potential Drug Interactions Between ALXN2080 and Rosuvastatin and Metformin in Healthy Adult ParticipantsCTID: NCT06160414Phase: Phase 1Status: CompletedDate: 2025-04-24
WO2024259085
WO2024137329
SYN
426
https://patentscope.wipo.int/search/en/detail.jsf?docId=US289331902&_cid=P10-MJJEYB-31207-1
SYN
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018160889&_cid=P10-MJJEK1-12570-1
PAT
- Aryl, heteroaryl and heterocyclic pharmaceutical compounds for the treatment of medical disordersPublication Number: JP-7390449-B2Priority Date: 2017-03-01Grant Date: 2023-12-01
- Aryl, heteroaryl, and heterocyclic pharmaceutical compounds for treatment of medical disordersPublication Number: US-11708351-B2Priority Date: 2017-03-01Grant Date: 2023-07-25
- Aryl, heteroaryl and heterocyclic pharmaceutical compounds for the treatment of medical disordersPublication Number: JP-2022174122-APriority Date: 2017-03-01
- Aryl, heteroaryl, and heterocyclic pharmaceutical compounds for the treatment of medical disordersPublication Number: KR-20190126831-APriority Date: 2017-03-01
- Aryl, heteroaryl, and heterocyclic pharmaceutical compounds for treatment of medical disordersPublication Number: US-11084800-B2Priority Date: 2017-03-01Grant Date: 2021-08-10
- Aryl, heteroary, and heterocyclic pharmaceutical compounds for treatment of medical disordersPublication Number: EP-3985002-A1Priority Date: 2017-03-01
- Aryl, heteroaryl, and heterocyclic pharmaceutical compounds for the treatment of medical disordersPublication Number: KR-102632860-B1Priority Date: 2017-03-01Grant Date: 2024-02-02
- Aryi, Heteroaryl, and Heterocyclic Pharmaceutical Compounds for Treatment of Medical DisordersPublication Number: US-2020071301-A1Priority Date: 2017-03-01
- Aryl, Heteroaryl and Heterocyclic Pharmaceutical Compounds for the Treatment of Medical DisordersPublication Number: CN-110603252-APriority Date: 2017-03-01
- Aryl, heteroaryl, and heterocyclic pharmaceutical compounds for treatment of medical disordersPublication Number: US-2022396563-A1Priority Date: 2017-03-01
- Ocular drug depot for complement-mediated disordersPublication Number: US-2023126447-A1Priority Date: 2020-03-10
- Ocular drug depot for complement-mediated disordersPublication Number: WO-2021183555-A1Priority Date: 2020-03-10
- Aryl, heteroaryl, and heterocyclic pharmaceutical compounds for treatment of medical disordersPublication Number: US-12162860-B2Priority Date: 2017-03-01Grant Date: 2024-12-10
- Aryl, heteroaryl, and heterocyclic pharmaceutical compounds for treatment of medical disordersPublication Number: US-2023357199-A1Priority Date: 2017-03-01
- Aryl, heteroary, and heterocyclic pharmaceutical compounds for treatment of medical disordersPublication Number: WO-2018160889-A1Priority Date: 2017-03-01
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////zoracopan, complement factor D inhibitor, ALXN-2080, ALXN 2080, E7799Y8LXY
Zopocianine
Zopocianine
CAS 2206660-94-6, NA SALT 2206660-95-7
MF C74H93N7O27S4, 1,640.83
L-Tyrosine, N-[[[(1S)-1,3-dicarboxypropyl]amino]carbonyl]-L-g-glutamyl-3-[2-(2-aminoethoxy)ethoxy]propanoyl-L-phenylalanyl-O-[6-[2-[1,3-dihydro-3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-2H-indol-2-ylidene]ethylidene]-2-[2-[3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-3H-indolium-2-yl]ethenyl]-1-cyclohexen-1-yl]-, inner salt
N-{[(1S)-1,3-dicarboxypropyl]carbamoyl}-L-γ-glutamyl3-[2-(2-aminoethoxy)ethoxy]propanoyl-L-phenylalanylO-[(6Ξ)-2-{(1Ξ)-2-[3,3-dimethyl-1-(4-sulfobutyl)-5-
sulfonato-3H-indol-1-ium-2-yl]ethen-1-yl}-6-{(2Ξ)-2-
[3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-1,3-dihydro-2Hindol-2-ylidene]ethylidene}cyclohex-1-en-1-yl]-Ltyrosine
diagnostic imaging agent, UD9V5S9M7A, OTL 0078, OTL 78
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/////////zopocianine, diagnostic imaging agent, UD9V5S9M7A, OTL 0078, OTL 78
Zomiradomide
Zomiradomide
CAS 2655656-99-6
MF C45H48F3N7O6S MW871.97
- N-[2-[4-[[6-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethyl]-2-azaspiro[3.3]heptan-2-yl]methyl]cyclohexyl]-5-(2-hydroxypropan-2-yl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide
- N-[2-[trans-4-[[6-[2-[[2-(2,6-Dioxo-3-piperidinyl)-2,3-dihydro-1,3-dioxo-1H-isoindol-4-yl]amino]ethyl]-2-azaspiro[3.3]hept-2-yl]methyl]cyclohexyl]-5-(1-hydroxy-1-methylethyl)-6-benzothiazolyl]-6-(trifluoromethyl)-2-pyridinecarboxamide
antineoplastic, IRAK degrader-1, AQ5UXV5646
Zomiradomide is an orally active PROTAC degrader for IRAK4 (DC50=6 nM), thereby inhibiting the NF-κB signaling pathway. Zomiradomide acts also as a molecular glue, recruiting Ikaros and Aiolos, and mediating their degradation (DC50 for Ikaros is 1 nM), thereby activating the type I IFN signaling pathway.
Zomiradomide is a small molecule protein degrader of interleukin-1 receptor-associated kinase 4 (IRAK4) and the immunomodulatory imide drug (IMiD) substrates Ikaros (IKZF1) and Aiolos (IKZF3), with potential immunomodulating and antineoplastic activities. Upon administration, zomiradomide modulates the E3 (ubiquitin) ligase and targets IRAK4, Ikaros and Aiolos for ubiquitination. This induces proteasome-mediated degradation of IRAK4, Ikaros and Aiolos. The degradation of IRAK4 inhibits IRAK4-mediated signaling and prevents the activation of IRAK4-mediated nuclear factor-kappa B (NF-kB) signaling and decreases the expression of inflammatory cytokines and certain pro-survival factors. This inhibits the proliferation of IRAK4-overactivated tumor cells, which are found in cells harboring MYD88 activating mutations or those with overactivated toll-like receptor (TLR) pathways. The degradation of the transcription factors Ikaros and Aiolos leads to a downregulation of other proteins, including interferon regulatory factor 4 (IRF4), which upregulates type I interferon signaling and further inhibits NF-kB activation. This leads to apoptosis and the inhibition of tumor cell proliferation. IRAK4, a serine/threonine-protein kinase that plays a key role in both the TLR and IL-1R signaling pathways, is activated though the adaptor protein MYD88 and links the TLR and IL-1R signaling pathway to the NF-kB pathway.
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022027058&_cid=P20-MJGJKA-81687-1
Example 1. Synthesis of N-[2-[4-[[6-[2-[[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]amino]ethyl]-2- azaspiro[3.3]heptan-2-yl]methyl]cyclohexyl]-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (Compound A)
[00349] To a solution of 4-[2-(2-azaspiro[3.3]heptan-6-yl)ethylamino]-2-(2,6-dioxo-3-piperidyl)isoindoline -1,3-dione (75.8 mg, 148 umol, TFA salt, Intermediate ATH) in THF (2 mL) was added TEA (15.0 mg, 148 umol), then the mixture stirred at 25 °C for 10 min. Next, HOAc (8.92 mg, 148 umol) and N-[2-(4-formylcyclohexyl)-5-(1-hydroxy-1-methyl-ethyl)-1,3-benzothiazol-6-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (73.0 mg, 148 umol, Intermediate BAX) were added to the mixture and the mixture was stirred at 25 °C for 20 minutes, then NaBH(OAc)3 (62.9 mg, 297 umol) was added to the mixture at 0 °C. The reaction mixture was stirred at 0-25 °C for 2 hours. On completion, the reaction mixture was quenched with H2O (1 mL) and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18150*25*10 um; mobile phase: [water(0.225%FA)-ACN]; B%: 31%-58%, 9 min) to give the title compound (59.1 mg, 41% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 11.09 (s, 1H), 9.06 (s, 1H), 8.49 – 8.44 (m, 1H), 8.38 (t, J = 8.0 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.88 (s, 1H), 7.58 (t, J = 8.0 Hz, 1H), 7.10 – 6.99 (m, 2H), 6.47 (t, J = 5.6 Hz, 1H), 6.07 (s, 1H), 5.05 (dd, J = 5.6, 12.8 Hz, 1H), 3.54 – 3.47 (m, 2H), 3.25 – 3.18 (m, 4H), 3.06 – 2.99 (m, 1H), 2.93 – 2.83 (m, 1H), 2.63 – 2.56 (m, 1H), 2.54 (s, 3H), 2.30 – 2.21 (m, 2H), 2.30 – 2.21 (m, 3H), 2.06 – 1.99 (m, 1H), 1.88 – 1.77 (m, 4H), 1.68 – 1.61 (m, 8H), 1.58 – 1.49 (m, 2H), 1.45 – 1.36 (m, 1H), 1.15 – 1.02 (m, 2H); LC-MS (ESI+) m/z 872.2 (M+H)+.
PAT
- Irak degraders and uses thereofPublication Number: US-2024131016-A1Priority Date: 2019-12-17
- Irak degraders and uses thereofPublication Number: EP-4076520-A1Priority Date: 2019-12-17
- IRAK degraders and uses thereofPublication Number: US-11779578-B2Priority Date: 2019-12-17Grant Date: 2023-10-10
- IRAK degraders and uses thereofPublication Number: US-11707457-B2Priority Date: 2019-12-17Grant Date: 2023-07-25
- Methods of treating mutant lymphomasPublication Number: US-2024316004-A1Priority Date: 2020-07-30
- Methods of treating mutant lymphomasPublication Number: US-2022054453-A1Priority Date: 2020-07-30
- Irak degraders and uses thereofPublication Number: US-2023144292-A1Priority Date: 2019-12-17
- Irak degraders and uses thereofPublication Number: WO-2021127190-A1Priority Date: 2019-12-17
- Irak degraders and uses thereofPublication Number: US-2021228562-A1Priority Date: 2019-12-17
- Irak4 degraders and uses thereofPublication Number: EP-4463166-A1Priority Date: 2022-01-14
- Methods of treating mutant lymphomasPublication Number: WO-2022027058-A1Priority Date: 2020-07-30
- Methods of treating mutated lymphomaPublication Number: CN-116133692-APriority Date: 2020-07-30
- Methods of treating mutant lymphomasPublication Number: US-11857535-B2Priority Date: 2020-07-30Grant Date: 2024-01-02
- Methods of treating mutant lymphomasPublication Number: EP-4188374-A1Priority Date: 2020-07-30
- Irak4 degraders and uses thereofPublication Number: WO-2024191788-A1Priority Date: 2023-03-10
- Formulations for treating cancerPublication Number: WO-2024163751-A1Priority Date: 2023-02-01
- Irak4 degraders and uses thereofPublication Number: WO-2024148049-A1Priority Date: 2023-01-04
- Irak4 degraders and uses thereofPublication Number: US-2023277519-A1Priority Date: 2022-01-14
- Irak4 degraders and uses thereofPublication Number: WO-2023137439-A1Priority Date: 2022-01-14
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/////////zomiradomide, antineoplastic, IRAK degrader-1, AQ5UXV5646
Zerencotrep
Zerencotrep
CAS 1628287-16-0
MF C23H20ClF3N4O5, MW 524.88
7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-3-methyl-8-[3-(trifluoromethoxy)phenoxy]purine-2,6-dione
7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-3-
methyl-8-[3-(trifluoromethoxy)phenoxy]-3,7-dihydro1H-purine-2,6-dione
transient receptor potential channel 4 and 5 (TRPC4, TRPC5) inhibitor, Pico 145, HC 608, HMIMSYLCWQ
Pico145 (HC-608) is a remarkable inhibitor of TRPC1/4/5 channels, inhibits (-)-englerin A-activated TRPC4/TRPC5 channels, with IC50s of 0.349 and 1.3 nM in cells, and shows no effect on TRPC3, TRPC6, TRPV1, TRPV4, TRPA1, TRPM2, TRPM8.
Zerencotrep is a small molecule drug. The usage of the INN stem ‘-cotrep’ in the name indicates that Zerencotrep is a transient receptor potential canonical channel 5 (TRPC5) antagonist. Zerencotrep has a monoisotopic molecular weight of 524.11 Da.
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014143799&_cid=P22-MJF454-30876-1
The following examples 7a through 7k were prepared using the method of example 6, step 1.
Example 7a 7-(4-chlorobenzyl)-l -(3-hydroxypropyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-l -purine-2,6(3H,7H)-dione
The title compound was prepared using the method of example 6, step 1 and purified
preparative HPLC to give 7-(4-chlorobenzyl)-l -(3-hydroxypropyl)-3-methyl-8-(3-
(trifluoromethoxy)phenoxy)-lH-purine-2,6(3H,7H)-dione (10 mg, 17.3% yield) as white solid. lH-NMR (CD3OD) δ 7.57-7.53(t, IH), 7.46-7.44(d, 2H), 7.37-7.33(m, 4H), 7.26-7.24(d, IH), 5.49(s, 2H), 4.13-4.09(t, IH), 3.64-3.60(t, 2H), 3.42(s, 3H), 1.89-1.86(m, 2H). LCMS retention time 3.059 min; LCMS MH+ 525.
PAT
- Side chain unsaturated 1α-hydroxyvitanim D homologsPublication Number: US-5250523-APriority Date: 1988-04-29Grant Date: 1993-10-05
- Antiviral methods utilizing ribofuranosylthiazolo[4,5-d]pyrimdine derivativesPublication Number: US-4880784-APriority Date: 1987-12-21Grant Date: 1989-11-14
- NEW NUCLEOSIDES AND NUCLEOTIDES AND PROCEDURES FOR THE PREPARATION.Publication Number: NO-893343-LPriority Date: 1987-12-21
- New amidino derivativesPublication Number: JP-H01131145-APriority Date: 1987-09-21
- Oligonucleotides, a process for preparing the same and their application as mediators of the action of interferonPublication Number: US-4476301-APriority Date: 1982-04-29Grant Date: 1984-10-09
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- Pico145 inhibits TRPC4-mediated mICAT and postprandial small intestinal motilityPublication Name: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapiePublication Date: 2023-12PMID: 37857250DOI: 10.1016/j.biopha.2023.115672
- Human TRPC5 structures reveal interaction of a xanthine-based TRPC1/4/5 inhibitor with a conserved lipid binding sitePublication Name: Communications BiologyPublication Date: 2020-11-23PMCID: PMC7683545PMID: 33230284DOI: 10.1038/s42003-020-01437-8
- Discovery of a Potent and Selective TRPC5 Inhibitor, Efficacious in a Focal Segmental Glomerulosclerosis ModelPublication Name: ACS Medicinal Chemistry LettersPublication Date: 2019-10-22PMCID: PMC6862342PMID: 31749913DOI: 10.1021/acsmedchemlett.9b00430
- Potent, selective, and subunit‐dependent activation of TRPC5 channels by a xanthine derivativePublication Name: British Journal of PharmacologyPublication Date: 2019-09-06PMCID: PMC6811774PMID: 31277085DOI: 10.1111/bph.14791
- Review of Transient Receptor Potential Canonical (TRPC5) Channel Modulators and DiseasesPublication Name: Journal of Medicinal ChemistryPublication Date: 2019-04-03PMID: 30943030DOI: 10.1021/acs.jmedchem.8b01954
///////////zerencotrep, Pico 145, HC 608, HMIMSYLCWQ
Zemprocitinib
Zemprocitinib
CAS 2417414-44-7
MF C16H19N5O2S MW 345.4 g/mol
N-[3-(3,5,8,10-tetrazatricyclo[7.3.0.02,6]dodeca-1,4,6,8,11-pentaen-3-yl)-1-bicyclo[1.1.1]pentanyl]propane-1-sulfonamide
N-[3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl]propane-1-sulfonamide
Janus kinase inhibitor, anti-inflammatory, LNK 01001, LG6MM3RP86
Zemprocitinib (also known as LNK01001) is a selective Janus kinase (JAK) 1 inhibitor, a type of small molecule drug being developed for inflammatory and autoimmune conditions like rheumatoid arthritis, atopic dermatitis, and ankylosing spondylitis. It works by blocking the JAK1 enzyme, reducing the inflammatory signals that cause these diseases, and has shown promising results in clinical trials, with development reaching Phase 3.
Key Aspects:
- Drug Class: JAK1 Inhibitor.
- Mechanism: Blocks Janus Kinase 1, a key enzyme in inflammatory pathways.
- Developer: Initially Lynk Pharmaceuticals.
- Potential Uses: Rheumatoid Arthritis, Atopic Dermatitis, Ankylosing Spondylitis, Psoriasis, Alopecia Areata.
- Development Stage: Reached Phase 3 clinical trials for several indications.
- Chemical Info: CAS: 2417414-44-7; Formula: C16H19N5O2S.
In Summary:
Zemprocitinib is an investigational drug targeting inflammation by inhibiting JAK1, with potential to treat various autoimmune disorders, showing strong efficacy in early clinical trials for conditions like rheumatoid arthritis.
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=US347660217&_cid=P21-MJDP3D-82397-1
Example 1
Step 1. 4-Chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1b)
Step 2. 4-Chloro-5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridine (1c)
Step 3. Tert-butyl 3-((5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)bicyclo[1.1.1]pentane-1-carboxylate (Id)
Step 4. Tert-butyl 3-((5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)amino)bicyclo[1.1.1]pentane-1-carboxylate (le)
Step 5. Tert-butyl 3-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)bicyclo[1.1.1]pentane-1-carboxylate (1f)
Step 6. 3-(6-Tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6LF)-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (1g)
Step 7. Tert-butyl (3-(6-tosylimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6LF)-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (1h)
Step 8. Tert-butyl (3-(imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (1i)
Step 9. 3-(Imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-amine 2,2,2-trifluoroacetate (1j)
Step 10. N-(3-(Imidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(6H)-yl)bicyclo[1.1.1]pentan-1-yl)propane-1-sulfonamide (1)
PAT
- Tricyclic janus kinase 1 inhibitors, and compositions and methods thereofPublication Number: ES-2993867-T3Priority Date: 2018-11-01Grant Date: 2025-01-10
- Tricyclic janus kinase 1 inhibitors, and compositions and methods thereofPublication Number: JP-2024147699-APriority Date: 2018-11-01
- Tricyclic janus kinase 1 inhibitors, and compositions and methods thereofPublication Number: EP-3856742-B1Priority Date: 2018-11-01Grant Date: 2024-10-02
- Tricyclic janus kinase 1 inhibitors, and compositions and methods thereofPublication Number: US-2022009927-A1Priority Date: 2018-11-01
- Tricyclic janus kinase 1 inhibitors, and compositions and methods thereofPublication Number: US-2023357247-A1Priority Date: 2018-11-01
- Tricyclic janus kinase 1 inhibitors, and compositions and methods thereofPublication Number: US-2023339950-A1Priority Date: 2018-11-01
- Tricyclic Janus kinase 1 inhibitors, and compositions and methods thereofPublication Number: AU-2019372677-B2Priority Date: 2018-11-01Grant Date: 2024-05-30
- Tricyclic janus kinase 1 inhibitors, and compositions and methods thereofPublication Number: TW-202432555-APriority Date: 2018-11-01
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///////////Zemprocitinib, Janus kinase inhibitor, anti-inflammatory, LNK 01001, LG6MM3RP86
Zemirciclib
Zemirciclib
CAS 2057509-72-3
MF C22H28ClN5O2, 429.9 g/mol
(1S,3R)-3-acetamido-N-[5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-
yl]cyclohexane-1-carboxamide
(1S,3R)-3-acetamido-N-[5-chloro-4-(5,5-dimethyl-4,6-dihydropyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl]cyclohexane-1-carboxamide
(1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide
cyclin-dependent kinase inhibitor, antineoplastic, AZD 4573, UNII-E5XSP3X68B
Zemirciclib is a selective, short-acting inhibitor of the serine/threonine cyclin-dependent kinase 9 (CDK9), the catalytic subunit of the RNA polymerase II (RNA Pol II) elongation factor positive transcription elongation factor b (PTEF-b; PTEFb), with potential antineoplastic activity. Upon intravenous administration, zemirciclib binds to and blocks the phosphorylation and kinase activity of CDK9, thereby preventing PTEFb-mediated activation of RNA Pol II, leading to the inhibition of gene transcription of various anti-apoptotic proteins. This induces cell cycle arrest and apoptosis, and leads to a reduction in tumor cell proliferation. CDK9 regulates elongation of transcription through phosphorylation of RNA polymerase II at serine 2 (p-Ser2-RNAPII). It is upregulated in various tumor cell types and plays a key role in the regulation of Pol II-mediated transcription of anti-apoptotic proteins. Tumor cells are dependent on anti-apoptotic proteins for their survival.
AZD-4573 is a small molecule drug with a maximum clinical trial phase of II and has 1 investigational indication.
- AZD4573 in Novel Combinations With Anti-cancer Agents in Patients With Advanced Blood CancerCTID: NCT04630756Phase: Phase 1/Phase 2Status: CompletedDate: 2025-04-09
- AZD4573 as Monotherapy or in Combinations With Anti-cancer Agents in Patients With r/r PTCL or r/r cHLCTID: NCT05140382Phase: Phase 2Status: CompletedDate: 2024-08-28
- Study to Assess Safety, Tolerability, Pharmacokinetics and Antitumor Activity of AZD4573 in Relapsed/Refractory Haematological MalignanciesCTID: NCT03263637Phase: Phase 1Status: CompletedDate: 2021-10-22
SYN
- Large-Scale Synthesis of AZD4573Publication Name: SynfactsPublication Date: 2022-05-17DOI: 10.1055/s-0041-1738312
- From Structure Modification to Drug Launch: A Systematic Review of the Ongoing Development of Cyclin-Dependent Kinase Inhibitors for Multiple Cancer TherapyPublication Name: Journal of Medicinal ChemistryPublication Date: 2022-04-29PMID: 35485642DOI: 10.1021/acs.jmedchem.1c02064
- Lessons Learned from Past Cyclin-Dependent Kinase Drug Discovery EffortsPublication Name: Journal of Medicinal ChemistryPublication Date: 2022-03-02PMID: 35235745DOI: 10.1021/acs.jmedchem.1c02190
- Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological MalignanciesPublication Name: Journal of Medicinal ChemistryPublication Date: 2020-12-11PMID: 33306391DOI: 10.1021/acs.jmedchem.0c01754
- A comprehensive insight on the recent development of Cyclic Dependent Kinase inhibitors as anticancer agentsPublication Name: European Journal of Medicinal ChemistryPublication Date: 2020-10-01PMID: 32707525DOI: 10.1016/j.ejmech.2020.112571
- Recent Developments in the Biology and Medicinal Chemistry of CDK9 Inhibitors: An UpdatePublication Name: Journal of Medicinal ChemistryPublication Date: 2020-08-31PMID: 32866383DOI: 10.1021/acs.jmedchem.0c00744
- AZD4573 Is a Highly Selective CDK9 Inhibitor That Suppresses MCL-1 and Induces Apoptosis in Hematologic Cancer CellsPublication Name: Clinical cancer research : an official journal of the American Association for Cancer ResearchPublication Date: 2020-02-14PMID: 31699827DOI: 10.1158/1078-0432.ccr-19-1853
- A New CDK9 Inhibitor on the Block to Treat Hematologic MalignanciesPublication Name: Clinical cancer research : an official journal of the American Association for Cancer ResearchPublication Date: 2020-02-14PMID: 31843752DOI: 10.1158/1078-0432.ccr-19-3670
- Cyclin dependent kinase (CDK) inhibitors as anticancer drugs: Recent advances (2015–2019)Publication Name: Bioorganic & Medicinal Chemistry LettersPublication Date: 2019-10-15PMID: 31477350DOI: 10.1016/j.bmcl.2019.126637
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2017001354&_cid=P22-MJC84G-87476-1
Example 14: (1S,3R)-3-acetamido-N-(5-chloro-4-(5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl)cyclohexanecarboxamide
PAT
- COMPOUNDS DERIVED FROM POLYCYCLIC AMIDE AS CDK9 INHIBITORS, COMPOSITION AND THEIR USESPublication Number: BR-122019013677-B1Priority Date: 2015-06-29
- Polycyclic amide derivatives as CDK9 inhibitorsPublication Number: KR-102663113-B1Priority Date: 2015-06-29Grant Date: 2024-05-02
- Methods of treating a ras protein-related disease or disorderPublication Number: US-2025049810-A1
- Chemical compoundsPublication Number: TW-I723028-BPriority Date: 2015-06-29Grant Date: 2021-04-01
- Chemical compoundsPublication Number: US-2021171541-A1Priority Date: 2015-06-29
- POLYCYCLIC AMIDA DERIVATIVES AS CDK9 INHIBITORSPublication Number: HR-P20211970-T1Priority Date: 2015-06-29
- Pyridine and pyrimidine derivativesPublication Number: US-11352369-B2Priority Date: 2015-06-29Grant Date: 2022-06-07
- Chemical compoundsPublication Number: US-2022340592-A1Priority Date: 2015-06-29
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/////////Zemirciclib, cyclin-dependent kinase inhibitor, antineoplastic, AZD 4573, UNII-E5XSP3X68B
Zelenirstat
Zelenirstat
CAS 1215011-08-7
MF C24H30Cl2N6O2S, 537.5 g/mol
2,6-dichloro-N-[1,5-dimethyl-3-(2-methylpropyl)-1Hpyrazol-4-yl]-4-[2-(piperazin-1-yl)pyridin-4-yl]benzene-1-sulfonamide
N-myristoyltransferase inhibitor, antineoplastic, PCLX 001, DDD86481, CCI 002, DDD 86481
Zelenirstat (PCLX-001) is an investigational, oral small-molecule drug that inhibits N-myristoyltransferases (NMTs), enzymes crucial for adding fatty acids to proteins, a process vital for cell signaling and membrane attachment. Developed by Pacylex Pharmaceuticals, it’s being tested for various cancers, showing promise in hematologic cancers like AML and lymphomas, as well as solid tumors, by disrupting cancer cell survival and growth, with early trials indicating good safety and potential efficacy.
How it works:
- Targets NMT enzymes: Zelenirstat blocks NMT1 and NMT2, preventing myristoylation (adding a fatty acid) to proteins.
- Disrupts cancer cell processes: This inhibition interferes with essential cell signaling and stability, especially in cancer cells where NMT expression is altered, leading to cell death (apoptosis).
- Affects mitochondrial function: It also disrupts mitochondrial complex I and oxidative phosphorylation, vital for leukemia stem cell survival, notes Pacylex Pharmaceuticals.
Development & Status:
- Orphan Drug Status: Granted for Acute Myeloid Leukemia (AML).
- Clinical Trials: A Phase 1 trial demonstrated good safety and early signs of activity in patients with advanced solid tumors and lymphomas, leading to further development.
- New Drug Class: It represents a novel approach to cancer treatment, distinct from many existing therapies.
Potential Applications:
- Acute Myeloid Leukemia (AML)
- B-cell Lymphomas (like Diffuse Large B-Cell Lymphoma)
- Colorectal Carcinoma
- Other cancers, including breast, lung, bladder, and pancreatic cancers, show sensitivity in preclinical models.
Zelenirstat, also known as PCLX-001, is an investigational new drug that is being evaluated for the treatment of cancer and as an antiviral agent. It is a small molecule inhibitor targets both N-myristoyltransferase 1 (NMT1) and N-myristoyltransferase 2 (NMT2) proteins, which are responsible for myristoylation. Its dual mechanism of action disrupts both cell signaling and energy production in cancer cells.
Zelenirstat is a strong pan-N myristoyl transferase inhibitor, which prevents addition of myristic acid into penultimate glycine of protein with myristoylation signal, and initially has been introduced as anti-tumor drug.[1][2][3] It has completed phase I clinical trial and is going through escalation phase.[4] Its prototype DDD85646 as well as other NMT inhibitors such as IMP-1088 have strong antiviral activities against viruses that required myristoylated proteins to complete their life cycle, including hemorrhagic viruses, such as lassa and argentinian virus, and pox viruses, such as vaccinia and monkeypox.[5][6]
Zelenirstat is an orally bioavailable inhibitor of the enzyme N-myristoyl transferase (NMT), with potential antineoplastic activity. Upon oral administration, zelenirstat targets and binds to NMT, especially NMT type 2 (NMT2). This prevents NMT-mediated signaling and myristoylation. This inhibits proliferation of certain cancer cells in which NMT expression is lost. Zelenirstat also inhibits B-cell receptor (BCR) signaling and reduces the levels of Src-family tyrosine kinases (SFKs). NMTs mediate myristoylation, a key process by which the fatty acid myristate is added to proteins and allows proteins to interact with cell membranes and become part of the cell signaling system. NMT expression is lost in numerous cancers, such as blood cancer cells, thereby making these cells more sensitive to zelenirstat compared to normal cells. The loss of NMT expression may promote tumorigenesis.
Mechanism of action
Zelenirstat acts by inhibiting NMT I and II enzymes, which are required to complete the myristoylation of proteins. Without myristoylation, these proteins are targeted for proteasomal degradation.[7]
PCLX-001 is a first-in-kind N-Myristoyltransferase (NMT) inhibitor being developed by [Pacylex Pharmaceuticals](https://pacylex.com). Current studies have shown that PCLX-001 works differently than other known cancer drugs and has high activity and positive results in breast, lung, bladder and pancreas cancers.
- Study of PCLX-001 in R/R Advanced Solid Malignancies and B-cell LymphomaCTID: NCT04836195Phase: Phase 1Status: CompletedDate: 2025-04-17
- Study of Oral PCLX-001 in R/R Acute Myeloid LeukemiaCTID: NCT06613217Phase: Phase 1Status: RecruitingDate: 2025-03-10
REF
- Novel, First-in-Human, Oral PCLX-001 Treatment in a Patient with Relapsed Diffuse Large B-Cell LymphomaPublication Name: Current oncology (Toronto, Ont.)Publication Date: 2022-03-13PMCID: PMC8947478PMID: 35323358DOI: 10.3390/curroncol29030158
- N-myristoyltransferase proteins in breast cancer: prognostic relevance and validation as a new drug targetPublication Name: Breast Cancer Research and TreatmentPublication Date: 2021-01-04PMCID: PMC7940342PMID: 33398478DOI: 10.1007/s10549-020-06037-y
- Targeting N-myristoylation for therapy of B-cell lymphomasPublication Name: Nature CommunicationsPublication Date: 2020-10-22PMCID: PMC7582192PMID: 33093447DOI: 10.1038/s41467-020-18998-1
- Emerging New Targets for the Treatment of Resistant Fungal InfectionsPublication Name: Journal of Medicinal ChemistryPublication Date: 2018-01-02PMID: 29294275DOI: 10.1021/acs.jmedchem.7b01413
- Interrogating the Roles of Post-Translational Modifications of Non-Histone ProteinsPublication Name: Journal of Medicinal ChemistryPublication Date: 2017-05-15PMID: 28505447DOI: 10.1021/acs.jmedchem.6b01817
SYN
DDD 86481
https://patentscope.wipo.int/search/en/detail.jsf?docId=US73438944&_cid=P12-MJAUPA-00022-1
INTERMEDIATE 23A
4-Bromo-2,6-dichloro-N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-benzenesulfonamide
EXAMPLE DDD86481
2,6-Dichloro-N-(3-isobutyl-1,5-dimethyl-1H-pyrazol-4-yl)-4-(2-piperazin-1-yl-pyridin-4-yl)-benzenesulfonamide
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2010026365&_cid=P12-MJAUOO-99381-1
PAT
N-myristoyl transferase inhibitors
Publication Number: WO-2010026365-A1
Priority Date: 2008-09-02
- N-myristoyl transferase inhibitorsPublication Number: ES-2546865-T3Priority Date: 2008-09-02Grant Date: 2015-09-29
- N-Myristoyl Transferase InhibitorsPublication Number: US-2011312921-A1Priority Date: 2008-09-02
- N-myristoyl transferase inhibitorsPublication Number: US-2016060224-A1Priority Date: 2008-09-02
- N-myristoyl transferase inhibitorsPublication Number: US-9156811-B2Priority Date: 2008-09-02Grant Date: 2015-10-13
- N-myristoyl transferase inhibitorsPublication Number: US-9828346-B2Priority Date: 2008-09-02Grant Date: 2017-11-28
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……
References
- Gamma JM, Liu Q, Beauchamp E, Iyer A, Yap MC, Zak Z, et al. (January 2025). “Zelenirstat Inhibits N-Myristoyltransferases to Disrupt Src Family Kinase Signaling and Oxidative Phosphorylation, Killing Acute Myeloid Leukemia Cells”. Molecular Cancer Therapeutics. 24 (1): 69–80. doi:10.1158/1535-7163.MCT-24-0307. PMC 11694064. PMID 39382188.
- Sangha R, Jamal R, Spratlin J, Kuruvilla J, Sehn LH, Beauchamp E, et al. (August 2024). “A first-in-human phase I trial of daily oral zelenirstat, a N-myristoyltransferase inhibitor, in patients with advanced solid tumors and relapsed/refractory B-cell lymphomas”. Investigational New Drugs. 42 (4): 386–393. doi:10.1007/s10637-024-01448-w. PMC 11327210. PMID 38837078.
- Sangha RS, Jamal R, Spratlin J, Kuruvilla J, Sehn LH, Weickert M, et al. (June 2024). “Final results of a first-in-human phase I dose escalation trial of daily oral zelenirstat, a n-myristoyltransferase inhibitor, in patients with advanced solid tumors and relapsed/refractory B-cell lymphomas”. Journal of Clinical Oncology. 42 (16_suppl): 3082. doi:10.1200/JCO.2024.42.16_suppl.3082. ISSN 0732-183X.
- Spratlin JL, Sangha RS, Jamal R, Beauchamp E, Berthiaume LG, Mackey JR (20 January 2024). “A first-in-human, open-label, phase I trial of daily oral zelenirstat, an NMT inhibitor, in patients with relapsed/refractory advanced cancer including gastrointestinal cancers”. Journal of Clinical Oncology. 42 (3_suppl): 129–129. doi:10.1200/jco.2024.42.3_suppl.129. Retrieved 19 January 2025.
- Witwit H, Betancourt CA, Cubitt B, Khafaji R, Kowalski H, Jackson N, et al. (August 2024). “Cellular N-Myristoyl Transferases Are Required for Mammarenavirus Multiplication”. Viruses. 16 (9): 1362. doi:10.3390/v16091362. PMC 11436053. PMID 39339839.
- Witwit H, Cubitt B, Khafaji R, Castro EM, Goicoechea M, Lorenzo MM, et al. (January 2025). “Repurposing Drugs for Synergistic Combination Therapies to Counteract Monkeypox Virus Tecovirimat Resistance”. Viruses. 17 (1): 92. doi:10.3390/v17010092. ISSN 1999-4915. PMC 11769280.
- Witwit H, Betancourt CA, Cubitt B, Khafaji R, Kowalski H, Jackson N, et al. (August 2024). “Cellular N-Myristoyl Transferases Are Required for Mammarenavirus Multiplication”. Viruses. 16 (9): 1362. doi:10.3390/v16091362. PMC 11436053. PMID 39339839.
| Clinical data | |
|---|---|
| Other names | PCLX-001 |
| Identifiers | |
| IUPAC name | |
| CAS Number | 1215011-08-7 |
| PubChem CID | 58561243 |
| DrugBank | DB15567 |
| ChemSpider | 35034199 |
| UNII | 5HY8BYC3Q6 |
| ChEMBL | ChEMBL3357685 |
| Chemical and physical data | |
| Formula | C24H30Cl2N6O2S |
| Molar mass | 537.50 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| SMILES | |
| InChI | |
////////zelenirstat, N-myristoyltransferase inhibitor, antineoplastic, PCLX 001, DDD86481, CCI 002, DDD 86481
Zavolosotine
Zavolosotine
CAS 2604416-66-0
MF C20H18F5N5O MW439.38
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide
4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)- N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine3-carboxamide
somatostatin receptor agonist, 275EAX4XXX
Zavolosotine (Compound 1) is an orally active agonist for somatostatin receptor type 5 (SST5) with EC50 <1 nM. Zavolosotine inhibits insulin and glucagon secretion, increases levels of glucagon in blood in rat model.
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2022177988&_cid=P20-MJ9E0I-92373-1
SYN
https://patentscope.wipo.int/search/en/detail.jsf?docId=US318018214&_cid=P20-MJ9DV5-88499-1
Example 4. 4-[(3S)-3-aminopyrrolidin-1-yl]-6-cyano-5-(3,5-difluorophenyl)-N-[(2S)-1,1,1-trifluoropropan-2-yl]pyridine-3-carboxamide (Compound 1-71)
| Step 4-1, preparation of tert-butyl (S)-(1-(2-chloro-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate: to a DMF (70 mL) solution was added 4,6-dichloronicotinaldehyde (6.8 g, 1.0 Eq, 39 mmol), tert-butyl (S)-pyrrolidin-3-ylcarbamate (7.6 g, 1.1 Eq, 41 mmol) and TEA (16 mL, 3.1 Eq, 120 mmol). The resulting mixture was stirred at 50° C. for 4 hours. The reaction crude was quenched with water (100 mL) and extracted with ethyl acetate (3×40 mL). The organic layers were combined, washed with brine, dried and concentrated under vacuum. The remaining residue was purified by silica gel chromatography eluting with ethyl acetate/petroleum ether (1/3) to afford tert-butyl (S)-(1-(2-chloro-5-formylpyridin-4-yl)pyrrolidin-3-yl)carbamate (5.3 g, 42%) as a yellow solid. MS (M+H) +=326.2. |
PAT
- Nonpeptide somatostatin type 5 receptor agonists and uses thereofPublication Number: US-2022144802-A1Priority Date: 2019-08-14
- Non-peptide somatostatin type 5 receptor agonists and uses thereofPublication Number: JP-2022544055-APriority Date: 2019-08-14
- Nonpeptide somatostatin type 5 receptor agonists and uses thereofPublication Number: US-11479540-B2Priority Date: 2019-08-14Grant Date: 2022-10-25
- Nonpeptide somatostatin type 5 receptor agonists and uses thereofPublication Number: TW-I841768-BPriority Date: 2019-08-14Grant Date: 2024-05-11
- Non-peptide somatostatin type 5 receptor agonists and uses thereofPublication Number: JP-7611893-B2Priority Date: 2019-08-14Grant Date: 2025-01-10
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///////////zavolosotine, somatostatin receptor agonist, 275EAX4XXX
Zamzetoclax
Zamzetoclax
CAS 2388470-64-0
MF C38H46ClN5O6S MW736.32
N-[(3′R,4S,6′R,7′S,8′E,11′S)-7-chloro-7′-methoxy-11′-methyl-13′,15′-dioxospiro[2,3-dihydro-1H-naphthalene-4,22′-20-oxa-13λ6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,13,16(25),17,19(24)-pentaene]-13′-yl]-3-methoxy-1-methylpyrazole-4-carboxamide
- 1H-Pyrazole-4-carboxamide, N-[(1’S,10S,12S,14E,16S,16aR,18aR)-6′-chloro-3′,4′,8,11,12,13,16,16a,17,18,18a,19-dodecahydro-16-methoxy-12-methyl-10-oxido-8-oxospiro[5,7-etheno-1H-10lambda4-cyclobut[i][1,4]oxazepino[3,4-f][1,2,7]thiadiazacyclohexadecine-2(3H),1′(2’H)-naphthalen]-10-yl]-3-methoxy-1-methyl-
- N-[(1’S,10S,12S,14E,16S,16aR,18aR)-6′-Chloro-3′,4′,8,11,12,13,16,16a,17,18,18a,19-dodecahydro-16-methoxy-12-methyl-10-oxido-8-oxospiro[5,7-etheno-1H-10lambda4-cyclobut[i][1,4]oxazepino[3,4-f][1,2,7]thiadiazacyclohexadecine-2(3H),1′(2’H)-naphthalen]-10-yl]-3-methoxy-1-methyl-1H-pyrazole-4-carboxamide
B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, RRS8GZU2UN
Zamzetoclax (compound 1) is a potential Mcl-1 inhibitor.
Publication Name: Journal of Medicinal Chemistry
Publication Date: 2023-04-28
PMID: 37114951
DOI: 10.1021/acs.jmedchem.2c01953
SYN
WO 2019/222112
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019222112&_cid=P12-MJ7Z15-98773-1
Example 154
[0447] Example 154 was synthesized in the same manner as Example 18 using 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid and Example 109. Example 109 (620 mg, 1.04 mmol) was dissolved in dichloromethane (12 mL). 3-Methoxy-1-methyl-1H-pyrazole-4-carboxylic acid (324 mg, 2.08 mmol, 2 equiv.) and N-(3-dimethylaminopropyl)-N¢-ethylcarbodiimide hydrochloride (400 mg, 2.08 mmol, 2 equiv.) were added. The reaction mixture was stirred for 5 minutes at room temperature before DMAP (253 mg, 2.08 mmol, 2 equiv.) was added in a single portion. The reaction mixture was stirred overnight at room temperature and the progress of the reaction was monitored by LCMS. Upon completion, the reaction mixture was concentrated under reduced pressure, and the residue was purified by Gilson reverse phase prep HPLC (60-100% ACN/H2O with 0.1% TFA) to give Example 154.1H NMR (400 MHz, methanol-d4) d 8.07 (s, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.22– 7.10 (m, 3H), 6.92 (d, J = 8.2 Hz, 1H), 6.20– 6.05 (m, 1H), 5.63 (dd, J = 15.5, 8.0 Hz, 1H), 4.10 (d, J = 12.0 Hz, 1H), 4.06 (s, 4H), 3.91– 3.83 (m, 1H), 3.82 (s, 3H), 3.79 (s, 1H), 3.72 (d, J = 14.4 Hz, 1H), 3.38 (d, J = 14.5 Hz, 1H), 3.30 (s, 3H), 3.09 (dd, J = 15.1, 10.0 Hz, 1H), 2.89– 2.72 (m, 2H), 2.51 (d, J = 26.7 Hz, 2H), 2.24 (dd, J = 10.9, 6.0 Hz, 2H), 2.12 (d, J = 13.7 Hz, 1H), 2.02– 1.70 (m, 4H), 1.54– 1.40 (m, 1H), 1.14 (d, J = 6.1 Hz, 3H). LCMS-ESI+ (m/z): calcd for C38H46ClN5O6S: 735.28; found: 735.94.
SYN
WO 2019/222112 discloses novel 3′,4,4′,5-tetrahydro-2H,2′H-spiro[benzo[b][1,4]oxazepine-3,1′-naphthalene] derivatives that are active against MCL-1. For example, Compound 1 (below) has been shown to be an effective MCL-1 inhibitor
SYN
SYN
PAT
- Mcl-1 inhibitorsPublication Number: US-2019352271-A1Priority Date: 2018-05-14
- Mcl-1 inhibitorsPublication Number: US-2020331870-A1Priority Date: 2018-05-14
- MCL-1 inhibitorsPublication Number: US-10988451-B2Priority Date: 2018-05-14Grant Date: 2021-04-27
- MCL-1 inhibitorsPublication Number: US-11643400-B2Priority Date: 2018-05-14Grant Date: 2023-05-09
- Mcl-1 inhibitorsPublication Number: US-2023312490-A1Priority Date: 2018-05-14
- Processes and intermediates for preparing mcl1 inhibitorsPublication Number: US-2023013713-A1Priority Date: 2019-11-26
- Processes and intermediates for preparing MCL1 inhibitorsPublication Number: US-11760736-B2Priority Date: 2019-11-26Grant Date: 2023-09-19
- Mcl1 inhibitorsPublication Number: US-2021171543-A1Priority Date: 2019-11-12
- Mcl1 inhibitorsPublication Number: US-2023348494-A1Priority Date: 2019-11-12
- MCL-1 inhibitorsPublication Number: US-10703733-B2Priority Date: 2018-05-14Grant Date: 2020-07-07
- Salts and polymorphs of certain mcl-1 inhibitorsPublication Number: US-2023357274-A1Priority Date: 2022-05-04
- Combination mcl-1 inhibitors with anti-body drug conjugatesPublication Number: US-2022409736-A1Priority Date: 2021-06-11
- Processes and intermediates for preparing mcl1 inhibitorsPublication Number: US-2022177409-A1Priority Date: 2020-11-19
- Processes and intermediates for preparing mcl1 inhibitorsPublication Number: US-2021179570-A1Priority Date: 2019-11-26
- Processes and intermediates for preparing MCL1 inhibitorsPublication Number: US-11325891-B2Priority Date: 2019-11-26Grant Date: 2022-05-10
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///////////zamzetoclax, B-cell lymphoma 2 (Bcl-2) inhibitor, antineoplastic, RRS8GZU2UN
New Drug Approvals 
