Lead Optimization of a 4-Aminopyridine Benzamide Scaffold To Identify Potent, Selective, and Orally Bioavailable TYK2 Inhibitors

Citations Over TimeTop 10% of 2013 papers

Abstract

Herein we report our lead optimization effort to identify potent, selective, and orally bioavailable TYK2 inhibitors, starting with lead molecule 3. We used structure-based design to discover 2,6-dichloro-4-cyanophenyl and (1R,2R)-2-fluorocyclopropylamide modifications, each of which exhibited improved TYK2 potency and JAK1 and JAK2 selectivity relative to 3. Further optimization eventually led to compound 37 that showed good TYK2 enzyme and interleukin-12 (IL-12) cell potency, as well as acceptable cellular JAK1 and JAK2 selectivity and excellent oral exposure in mice. When tested in a mouse IL-12 PK/PD model, compound 37 showed statistically significant knockdown of cytokine interferon-γ (IFNγ), suggesting that selective inhibition of TYK2 kinase activity might be sufficient to block the IL-12 pathway in vivo.

Related Papers

• → Discovery and optimization of piperidyl benzamide derivatives as a novel class of 11β-HSD1 inhibitors(2009)28 cited
• → Discovery and SAR study of 3-(tert-butyl)-4-hydroxyphenyl benzoate and benzamide derivatives as novel farnesoid X receptor (FXR) antagonists(2015)8 cited
• Note Synthesis and antibacterial activity of benzamides and sulfonamide derived from 2- amino-5-bromo/nitropyridine against bacterial strains isolated from clinical patients(2011)
• → N-(4-Methylphenyl)benzamide(2007)7 cited
• → Synthesis of N‐(2,3‐dihydro‐1‐[14C]methyl‐2‐oxo‐5‐phenyl‐1H‐1,4‐benzodiazepin‐3‐yl)‐benzamide and N‐(2,3‐dihydro‐1‐[14C]methyl‐2‐oxo‐5‐phenyl‐1H‐1,4‐benzodiazepin‐3‐yl)‐N‐[14C]methyl‐benzamide as novel carbon‐14 labelled CCK antagonists(2002)6 cited