Ontunisertib

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Ontunisertib

CAS 2647949-48-0

MFC27H21F2N5O MW469.5 g/mol

N-[(2,6-difluorophenyl)methyl]-2-[3-(6-methyl-2-pyridinyl)-4-quinolin-4-ylpyrazol-1-yl]acetamide

N-(2,6-difluorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

N-[(2,6-difluorophenyl)methyl]-2-[3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl]acetamide
serine/threonine kinase inhibitor, AGMB 129, SF6HGC94LK

Ontunisertib (AGMB-129) is an experimental, orally active small-molecule drug developed by Agomab Therapeutics to treat Fibrostenosing Crohn’s Disease (FSCD). It acts as a highly selective inhibitor of ALK5 (also known as Transforming Growth Factor-beta type I receptor or TGF-β RI).

Mechanism of Action

Local Targeting: Designed to act specifically within the gastrointestinal (GI) tract.
High Tissue Exposure: Provides high local exposure in inflamed and scarred intestinal tissues.
Liver Inactivation: Undergoes rapid first-pass metabolism in the liver immediately after GI absorption.
Safety Feature: Converts into an inactive metabolite to prevent systemic exposure and avoid cardiac toxicity.

Clinical Development Status

FDA Status: Granted Fast Track Designation by the U.S. FDA.
Phase 2a Results: Successfully completed the STENOVA clinical trial. Results demonstrated excellent safety, high local tissue penetration, and positive structural improvements in bowel strictures.
Phase 2b Trial: Enrolling patients for the global, 52-week NOV-ERA trial to test multiple doses against a placebo. The primary goal is assessing the endoscopically confirmed widening of narrowed intestinal strictures

NOV-ERA – A Clinical Trial to Assess the Efficacy and Safety of Ontunisertib Compared to Placebo in Patients With Fibrostenosing Crohn’s DiseaseCTID: NCT07683325Phase: Phase 2Status: Not yet recruitingDate: 2026-07-06
Human Mass Balance Study of [14C] Ontunisertib in Healthy VolunteersCTID: NCT07672574Phase: Phase 1Status: Not yet recruitingDate: 2026-06-29
A Multiple Ascending Dose Study With AGMB-129 in Healthy ParticipantsCTID: NCT07118878Phase: Phase 1Status: CompletedDate: 2025-11-21
STENOVA – A Study to Evaluate Safety, Tolerability, PK and PD of AGMB-129 in Patients With Fibrostenotic Crohn’s DiseaseCTID: NCT05843578Phase: Phase 2Status: Active, not recruitingDate: 2025-11-21
Drug-Drug Interaction Study With AGMB-129 and Midazolam in Healthy ParticipantsCTID: NCT05937386Phase: Phase 1Status: CompletedDate: 2024-06-18

SYN

US12297186, Example 24

SYN

[WO2021105317A1]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2021105317&_cid=P20-MRPQUQ-14721-1

Example 24: N-(2,6-difluorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1 -yl)acetamide

¹H-NMR (300 MHz, DMSO-d₆): δ = 8.84 (d, J = 4.4 Hz, 1H), 8.76 (t, J = 5.3 Hz, 1H), 8.11-7.97 (m, 2H), 7.75-7.28 (m, 7H), 7.13 (t, J = 7.8 Hz, 2H), 6.97 (d, J = 7.5 Hz, 1 H), 4.99 (s, 2H), 4.43 (d, J = 5.3 Hz, 2H), 1.83 (s, 3H).

HPLC-MS: Rt 17.513 m/z 470.0 [M+H]⁺.

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2025176835&_cid=P20-MRPR39-19345-1

Potent inhibitors of TGFpRII-TGFpRI (ALK5) have been described in W02021/105317 including the compound (/V-(2,6-difluorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1/7-pyrazol-1-yl)acetamide) which is the compound of formula (I) as shown below (see Example 24):