DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Avenciguat
Avenciguat, 1579514-06-9
BI-685509, 582.7 g/mol, C34H38N4O5
UNII ZA7KTB4PSP
5-ethoxy-1-[6-[3-methyl-2-[[5-methyl-2-(oxan-4-yl)-3,4-dihydro-1H-isoquinolin-6-yl]methoxy]phenyl]pyridin-2-yl]pyrazole-4-carboxylic acid
Avenciguat (BI-685509) is a potent and orally active sGC activator. Avenciguat restores cyclic guanosine monophosphate (cGMP) and improves functionality of nitric oxide (NO) pathways. Avenciguat can be used in research of chronic kidney disease (CKD) and diabetic kidney disease (DKD).
Avenciguat is under investigation in clinical trial NCT05282121 (A Study to Test Whether BI 685509 Alone or in Combination With Empagliflozin Helps People With Liver Cirrhosis Caused by Viral Hepatitis or Non-alcoholic Steatohepatitis (NASH) Who Have High Blood Pressure in the Portal Vein (Main Vessel Going to the Liver)).
Avenciguat (development name BI 685509) is a soluble guanylate cyclase activator developed by Boehringer Ingelheim for kidney disease,[1][2] and cirrhosis.[3][4][5]
SCHEME
Ref
PAPER
Journal of Pharmacology and Experimental Therapeutics (2023), 384(3), 382-39
PATENT
Boehringer Ingelheim International GmbH
WO2014039434
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014039434&_cid=P12-M29UB4-37937-1
PATENT
US20230293513
WO2020011804
| Clinical data | |
|---|---|
| Other names | BI 685509 |
| Legal status | |
| Legal status | Investigational |
| Identifiers | |
| showIUPAC name | |
| CAS Number | 1579514-06-9 |
| PubChem CID | 89992620 |
| UNII | ZA7KTB4PSP |
| Chemical and physical data | |
| Formula | C34H38N4O5 |
| Molar mass | 582.701 g·mol−1 |
| 3D model (JSmol) | Interactive image |
| showSMILES | |
| showInChI | |
^ Cherney, David Z. I.; de Zeeuw, Dick; Heerspink, Hiddo J. L.; Cardona, Jose; Desch, Marc; Wenz, Arne; Schulze, Friedrich; Nangaku, Masaomi (August 2023). “Safety, tolerability, pharmacodynamics and pharmacokinetics of the soluble guanylyl cyclase activator BI 685509 in patients with diabetic kidney disease: A randomized trial”. Diabetes, Obesity and Metabolism. 25 (8): 2218–2226. doi:10.1111/dom.15099. PMID 37232058. S2CID 258909393.
^ Reinhart, Glenn A.; Harrison, Paul C.; Lincoln, Kathleen; Chen, Hongxing; Sun, Peng; Hill, Jon; Qian, Hu Sheng; McHugh, Mark C.; Clifford, Holly; Ng, Khing Jow; Wang, Hong; Fowler, Danielle; Gueneva-Boucheva, Kristina; Brenneman, Jehrod B.; Bosanac, Todd; Wong, Diane; Fryer, Ryan M.; Sarko, Chris; Boustany-Kari, Carine M.; Pullen, Steven S. (March 2023). “The Novel, Clinical-Stage Soluble Guanylate Cyclase Activator BI 685509 Protects from Disease Progression in Models of Renal Injury and Disease”. Journal of Pharmacology and Experimental Therapeutics. 384 (3): 382–392. doi:10.1124/jpet.122.001423. PMID 36507845. S2CID 254387173.
^ Lawitz, Eric J.; Reiberger, Thomas; Schattenberg, Jörn M.; Schoelch, Corinna; Coxson, Harvey O.; Wong, Diane; Ertle, Judith (November 2023). “Safety and pharmacokinetics of BI 685509, a soluble guanylyl cyclase activator, in patients with cirrhosis: A randomized Phase Ib study”. Hepatology Communications. 7 (11). doi:10.1097/HC9.0000000000000276. PMC 10615399. PMID 37889522.
^ Jones, Amanda K.; Chen, Hongxing; Ng, Khing Jow; Villalona, Jorge; McHugh, Mark; Zeveleva, Svetlana; Wilks, James; Brilisauer, Klaus; Bretschneider, Tom; Qian, Hu Sheng; Fryer, Ryan M. (July 2023). “Soluble Guanylyl Cyclase Activator BI 685509 Reduces Portal Hypertension and Portosystemic Shunting in a Rat Thioacetamide-Induced Cirrhosis Model”. Journal of Pharmacology and Experimental Therapeutics. 386 (1): 70–79. doi:10.1124/jpet.122.001532. PMID 37230799. S2CID 258909514.
^ Reiberger, Thomas; Berzigotti, Annalisa; Trebicka, Jonel; Ertle, Judith; Gashaw, Isabella; Swallow, Ros; Tomisser, Andrea (24 April 2023). “The rationale and study design of two phase II trials examining the effects of BI 685509, a soluble guanylyl cyclase activator, on clinically significant portal hypertension in patients with compensated cirrhosis”. Trials. 24 (1): 293. doi:10.1186/s13063-023-07291-3. PMC 10123479. PMID 37095557.
////////////Avenciguat, 1579514-06-9, BI 685509,
VALILTRAMIPROSATE
VALILTRAMIPROSATE
1034190-08-3
- (S)-3-(2-Amino-3-methylbutanamido)propane-1-sulfonic acid
- BLU8499
- WHO 11912
| Molecular Weight | 238.30 |
|---|---|
| Formula | C8H18N2O4S |
| CAS No. | 1034190-08-3 |
ALZ-801
Synonyms: valiltramiprosate, NRM-8499, homotaurine prodrug, 3-APS
This is a prodrug of homotaurine, a modified amino acid previously developed under the names tramiprosate and Alzhemed™. ALZ-801 is converted to homotaurine in vivo, but is more easily absorbed and lasts longer in the blood than tramiprosate.
Tramiprosate was reported to inhibit Aβ42 aggregation into toxic oligomers (Gervais et al., 2007; Kocis et al., 2017). Both ALZ-801 and tramiprosate are metabolized to 3-sulfopranpanoic acid (3-SPA), which is normally found in brain and also inhibits Aβ42 aggregation (Hey et al., 2018). A more recent study found that homotaurine activates GABA receptors, and suggests an alternative mechanism of action for ALZ-801 (Meera et al., 2023).
After tramiprosate failed in Phase 3, its maker, NeuroChem, marketed it as a nutritional supplement. Years later, a subgroup analysis of the trial data indicated a potential positive effect in participants who carried two copies of ApoE4 (Abushakra et al., 2016; Abushakra et al., 2017). Alzheon licensed ALZ-801 from NeuroChem and is developing it for Alzheimer’s disease.
ALZ-801 is a potent and orally available small-molecule β-amyloid (Aβ) anti-oligomer and aggregation inhibitor, valine-conjugated proagent of Tramiprosate with substantially improved PK properties and gastrointestinal tolerability compared with the parent compound. ALZ-801 is an advanced and markedly improved candidate for the treatment of alzheimer’s disease.
SCHEME
REF 1
US20080146642
https://patents.google.com/patent/US20080146642A1/en
HCL WATER, Dowex™ Marathon™ C ion-exchange column
General/Typical Procedure: [0311] (i) The solid material was dissolved in water (25 mL). The solution was passed through a Dowex™ Marathon™ C ion-exchange column (strongly acidic, 110 g (5 eq), prewashed). The strong acidic fractions were combined and treated with concentrated HCl (10 mL). The mixture was stirred at 50° C. for 30 minutes, and then was concentrated to dryness. The residual material was co-evaporated with EtOH (ethanol) to completely remove water. EtOH (100 mL) was added to the residue. The mixture was stirred at reflux for 1 h, and then cooled to room temperature. The solid material was collected by filtration. The solid material was dissolved in water (10 mL). The solution was added drop wise to EtOH (100 mL). The product slowly crystallized. The suspension was stirred at room temperature for 30 minutes. The solid material was collected by filtration and it was dried in a vacuum oven (60° C.). ID A2. 1H NMR (D2O).δ. 0.87-0.90 (m, 6H), 1.83 (qt, J = 7.2 Hz, 2H), 2.02-2.09 (m, 1H), 2.79 (t, J = 7.8 Hz, 2H), 3.20-3.29 (m, 2H), 3.60 (d, J = 6.3 Hz, 2H); 13C NMR (D2O).δ. 17.20, 17.77, 24.11, 30.00, 38.29, 48.63, 58.96, 169.35; m/z 237 (M-1).
- [1]. John A. Hey, et al. Discovery and Identification of an Endogenous Metabolite of Tramiprosate and Its Prodrug ALZ-801 that Inhibits Beta Amyloid Oligomer Formation in the Human Brain. CNS Drugs. 2018; 32(9): 849–861.[2]. Hey JA, et al. Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer’s Disease. Clin Pharmacokinet. 2018 Mar;57(3):315-333. [Content Brief]
////////VALILTRAMIPROSATE, ALZ-801, ALZ 801, BLU 8499, WHO 11912
VICATERTIDE
VICATERTIDE
1251838-01-3
L-Leucyl-L-glutaminyl-L-valyl-L-valyl-L-tyrosyl-L-leucyl-L-histidine
C42H66N10O10
L-Histidine, L-leucyl-L-glutaminyl-L-valyl-L-valyl-L-tyrosyl-L-leucyl- (ACI)
871.04
SB-01, HY-P5542, CS-0887146
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-amino-4-methylpentanoyl]amino]-5-oxopentanoyl]amino]-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-3-(1H-imidazol-5-yl)propanoic acid
- L-Leucyl-L-glutaminyl-L-valyl-L-valyl-L-tyrosyl-L-leucyl-L-histidine (ACI)
- 1: PN: KR983182 SEQID: 1 claimed sequence
- Vevoctadekin
- LQVVYLH
Vicatertide is a TGF beta-1 inhibitor[1].
KR983182
SEQ ID NO: 1 (LQVVYLH: SEQ ID NO: 1)
<Example 1> Preparation of peptides
A peptide having the amino acid sequence of SEQ ID NO: 1 (LQVVYLH: SEQ ID NO: 1) was produced by Peptron Inc. Specifically, coupling was performed one by one starting from the C-terminus using the Fmoc SPPS (9-Fluorenylmethyloxycarbonyl solid phase peptide synthesis) method using an automatic synthesizer (ASP48S, Peptron Inc).
NH 2 -His(Trt)-2-chloro-Trityl Resin , in which the first amino acid at the C-terminus of the peptide was attached to the resin, was used. All amino acid raw materials used in peptide synthesis have the N-terminus protected by Fmoc, and all residues are trityl (Trt), t-butyloxycarbonyl (Boc), t-butyl (t-Bu), etc., which are removed by acid. The protected one was used. As a coupling reagent, HBTU (2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate)/HOBt (Hydroxxybenzotriazole)/NMM (N-methylmorpholine) was used. (1) Protected amino acid (8 equivalents) and coupling reagent HBTU (8 equivalents)/HOBt (8 equivalents)/NMM (16 equivalents) were dissolved in DMF (Dimethylformamide) and added, followed by reaction at room temperature for 2 hours. (2) Fmoc removal was performed twice for 5 minutes at room temperature by adding 20% piperidine in DMF. After repeating reactions (1) and (2) to create the basic peptide skeleton, TFA (trifluoroacetic acid)/EDT (1,2-ethanedithiol)/Thioanisole/TIS (triisopropylsilane)/H 2 O=90/ 2.5 / Peptides were separated from the resin using 2.5/2.5/2.5. After purification by reverse phase HPLC using a Vydac Everest C18 column (250 mm × 22 mm, 10 μm), water-acetonitrile linear gradient (10~75% ( v/v) of acetonitrile) method. The molecular weight of the purified peptide was confirmed using LC/MS (Agilent HP1100 series) and lyophilized.
Ref
[1]. WHO D rug Information. Vol. 37, No. 2, 2023.
////VICATERTIDE, SB-01, SB 01, HY P5542, CS 0887146
Vorbipiprant
Vorbipiprant,
CR6086
1417742-86-9
4-[1-[[[(5R)-6-[[4-(Trifluoromethyl)phenyl]methyl]-6-azaspiro[2.5]oct-5-yl]carbonyl]amino]cyclopropyl]benzoic acid
Benzoic acid, 4-[1-[[[(5R)-6-[[4-(trifluoromethyl)phenyl]methyl]-6-azaspiro[2.5]oct-5-yl]carbonyl]amino]cyclopropyl]-
| Molecular Weight | 472.50 |
|---|---|
| Formula | C26H27F3N2O3 |
Vorbipiprant (CR6086) is an EP4 receptor antagonist, serving as a targeted immunomodulator. Thus, Vorbipiprant is also a potential immune checkpoint inhibitor, to turn cold tumors into hot tumors. Vorbipiprant also antagonizes PGE2-stimulated cAMP production (IC50=22 nM). Vorbipiprant exhibit striking DMARD effects in rodents, and anti-inflammatory activity to inhibt immune-mediated inflammatory diseases.
SCHEME
PATENT
Rottapharm S.p.A.
World Intellectual Property Organization, WO2013004290
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013004290&_cid=P10-M25P3U-15334-1
Example 7: 4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoic acid (single unknown enantiomer) (E7)
Procedure A:
The title compound (E7) (54 mg) was prepared according to the general procedure for esters hydrolysis (Method B) starting from methyl 4-(1 -(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate (D122b) (100mg). (LiOH: 4 eq; Reaction time: 18 hrs; RT)
MS: (ES/+) m/z: 473.4 [MH+] C26H27F3N2O3 requires 472.20
Chiral HPLC: [DAICEL AD-H; Mobile phase A: 90% n-heptane (+0.2% TFA), B: 10% EtOH; DAD: 245 nm]: Peak retention time: 18.97 min.
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.97 (d, J = 8.0 Hz, 2 H), 7.74 – 7.35 (m, 5 H), 7.26 (br. s., 1 H), 3.86 (d, J = 14.1 Hz, 1 H), 3.38 (d, J = 14.1 Hz, 1 H), 3.08 (d, J = 7.8 Hz, 1 H), 2.91 (d, J = 9.8 Hz, 1 H), 2.27 (br. s., 1 H), 2.05 (t, J = 1 1 .2 Hz, 1 H), 1 .84 (br. s., 1 H), 1 .50 – 1 .24 (m, 4 H), 1 .14 (br. s., 1 H), 0.98 (d, J = 12.7 Hz, 1 H), 0.53 – 0.23 (m, 4 H)
Procedure B:
methyl 4-(1 -(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate (D123)) (17.7 g, 36.38 mmol) was partitioned between dioxane (485 ml) and water (242 ml) prior addition of LiOH H2O (6.1 g,
145.5 mmol). The mixture was stirred at RT for 10 hrs. Water (200 ml) was added followed by addition of acetic acid (5.27 ml). Dioxane was evaporated off and acetic acid was added until the pH of the aqueous solution reached the value of ~ 4. The white solid was filtered from the reaction and dried under vacuum overnight then 24 hrs under vacuum at 40 °C affording the title compound (E7) (16.7g).
MS: (ES/+) m/z: 473.3 [MH+] C26H27F3N203 requires 472.20
Chiral HPLC: [DAICEL AD-H; Mobile phase A: 90% n-heptane (+0.2% TFA), B: 10% EtOH; DAD: 245 nm]: Peak retention time: 19.07 min.
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.92 – 12.51 (m, 1 H), 8.83 – 8.62 (m, 1 H), 7.85 – 7.75 (m, 2 H), 7.74 – 7.57 (m, 4 H), 7.26 – 7.14 (m, 2 H), 3.87 – 3.72 (m, 1 H), 3.27 – 3.20 (m, 1 H), 2.99 – 2.86 (m, 1 H), 2.79 – 2.69 (m, 1 H), 2.19 – 1 .98 (m, 2 H), 1 .86 – 1 .70 (m, 1 H), 1 .32 – 1 .07 (m, 5 H), 0.94 – 0.82 (m, 1 H), 0.46 -0.17 (m, 4 H).
//////////Vorbipiprant, CR 6086
New Drug Approvals 
