Selonsertib

• CAT Number: I001734
• CAS Number: 1448428-04-3
• Molecular Formula: C₂₄H₂₄FN₇O
• Molecular Weight: 445.50
• Purity: ≥95%
• Synonyms: 5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide
• Target: ASK1
• Solubility: DMSO ≥ 31 mg/mL
• Storage: Store at -20°C
• IUPAC Name: 5-(4-cyclopropylimidazol-1-yl)-2-fluoro-4-methyl-N-[6-(4-propan-2-yl-1,2,4-triazol-3-yl)pyridin-2-yl]benzamide
• InChI: InChI=1S/C24H24FN7O/c1-14(2)32-13-27-30-23(32)19-5-4-6-22(28-19)29-24(33)17-10-21(15(3)9-18(17)25)31-11-20(26-12-31)16-7-8-16/h4-6,9-14,16H,7-8H2,1-3H3,(H,28,29,33)
• InChIKey: YIDDLAAKOYYGJG-UHFFFAOYSA-N
• SMILES: CC1=CC(=C(C=C1N2C=C(N=C2)C3CC3)C(=O)NC4=CC=CC(=N4)C5=NN=CN5C(C)C)F

Selonsertib（Cat No.:I001734）is a selective inhibitor of apoptosis signal-regulating kinase 1 (ASK1), a key mediator of cellular stress and inflammation. ASK1 activation is associated with various pathological conditions, including fibrosis, inflammation, and cell death. By inhibiting ASK1, Selonsertib reduces inflammatory cytokine production and fibrosis, making it a potential therapeutic agent for chronic diseases like non-alcoholic steatohepatitis (NASH) and diabetic kidney disease. It has been studied for its ability to halt the progression of liver and renal fibrosis, providing a valuable tool in the research of ASK1-related pathways and their role in chronic inflammatory conditions.

Overview of Clinical Research

Originator: Gilead Sciences
Class: Benzamides; Cardiovascular therapies; Imidazoles; Pyridines; Triazoles
Mechanism of Action: MAP kinase kinase kinase 5 inhibitors
Orphan Drug Status: No

New Molecular Entity: Yes

Highest Development Phases: Phase III Non-alcoholic steatohepatitis

Reference

1. Hepatology. 2017 Sep 11. doi: 10.1002/hep.29514. [Epub ahead of print]
The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: A randomized, phase 2 trial.
Loomba R(1), Lawitz E(2), Mantry PS(3), Jayakumar S(4), Caldwell SH(5), Arnold H(6), Diehl AM(7), Djedjos CS(8), Han L(8), Myers RP(8), Subramanian GM(8), McHutchison JG(8), Goodman ZD(9), Afdhal NH(10), Charlton MR(11); GS-US-384-1497 Investigators.
Author information:
(1)University of California at San Diego, San Diego, CA. (2)Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX. (3)The Liver Institute at Methodist Dallas, Dallas, TX. (4)University of Calgary, Calgary, AB, Canada. (5)University of Virginia, Charlottesville, VA. (6)Gastroenterology Consultants of San Antonio, San Antonio, TX. (7)Duke Clinical Research Institute, Durham, NC. (8)Gilead Sciences, Inc., Foster City, CA. (9)Inova Fairfax Hospital, Falls Church, VA. (10)Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. (11)Intermountain Medical Center, Salt Lake City, UT.
Inhibition of apoptosis signal-regulating kinase 1, a serine/threonine kinase, leads to improvement in inflammation and fibrosis in animal models of nonalcoholic steatohepatitis. We evaluated the safety and efficacy of selonsertib, a selective inhibitor of apoptosis signal-regulating kinase 1, alone or in combination with simtuzumab, in patients with nonalcoholic steatohepatitis and stage 2 or 3 liver fibrosis. In this multicenter phase 2 trial, 72 patients were randomized to receive 24 weeks of open-label treatment with either 6 or 18 mg of selonsertib orally once daily with or without once-weekly injections of 125 mg of simtuzumab or simtuzumab alone. The effect of treatment was assessed by paired pretreatment and posttreatment liver biopsies, magnetic resonance elastography, magnetic resonance imaging-estimated proton density fat fraction, quantitative collagen content, and noninvasive markers of liver injury. Due to the lack of effect of simtuzumab on histology or selonsertib pharmacokinetics, selonsertib groups with and without simtuzumab were pooled. After 24 weeks of treatment, the proportion of patients with a one or more stage reduction in fibrosis in the 18-mg selonsertib group was 13 of 30 (43%; 95% confidence interval, 26-63); in the 6-mg selonsertib group, 8 of 27 (30%; 95% confidence interval, 14-50); and in the simtuzumab-alone group, 2 of 10 (20%; 95% confidence interval, 3-56). Improvement in fibrosis was associated with reductions in liver stiffness on magnetic resonance elastography, collagen content and lobular inflammation on liver biopsy, as well as improvements in serum biomarkers of apoptosis and necrosis. There were no significant differences in adverse events between the treatment groups.CONCLUSION: These findings suggest that selonsertib may reduce liver fibrosis in patients with nonalcoholic steatohepatitis and stage 2-3 fibrosis. (Hepatology 2017).