Abstract
Studies conducted with the goal of discovering a second-generation platelet-activating factor (PAF) antagonist have identified a novel class of potent and orally active antagonists which have high aqueous solubility and long duration of action in animal models. The compounds arose from the combination of the lipophilic indole portion of Abbott's first-generation PAF antagonist ABT-299 (2) with the methylimidazopyridine heterocycle moiety of British Biotechnology's BB-882 (1) and possess the positive attributes of both of these clinical candidates. Structure-activity relationship (SAR) studies indicated that modification of the indole and benzoyl spacer of lead compound 7b gave analogues that were more potent, longer-lived, and bioavailable and resulted in the identification of 1-(N, N-dimethylcarbamoyl)-4-ethynyl-3-[3-fluoro-4-[(1H-2-methylimidazo[4,5-c] pyrid-1-yl)methyl]benzoyl]indole hydrochloride (ABT-491, 22 m.HCl) which has been evaluated extensively and is currently in clinical development.
Citations
Apr 15, 2008·Molecular Diversity·Christopher Hulme, Yeon-Sun Lee
Sep 8, 1999·Mutation Research·R D Snyder, L Strekowski
Oct 30, 2007·Bioorganic & Medicinal Chemistry Letters·Gao-Jun FanByung Hoon Han
Aug 30, 2012·Chemistry : a European Journal·Yuuya OokuboAtsuhiro Osuka
Apr 10, 2003·Journal of Enzyme Inhibition and Medicinal Chemistry·Anne BretecheJean-Yves Petit
Oct 2, 2020·Organic & Biomolecular Chemistry·Shi-Biao TangYa-Fei Ji
May 29, 2018·Nature Structural & Molecular Biology·Can CaoBeili Wu
May 3, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Otto LindemannAlbrecht Schwab
May 15, 2002·Journal of Combinatorial Chemistry·Kazuo Yamazaki, Yoshinori Kondo
Apr 16, 2004·Journal of Medicinal Chemistry·Charles A BlumStéphane De Lombaert
Aug 25, 2001·Journal of Medicinal Chemistry·E CarcellerJ Forn
Mar 15, 2011·The Journal of Organic Chemistry·Viktor O IaroshenkoPeter Langer
Oct 23, 2004·The Journal of Organic Chemistry·Jeffrey T KuetheIan W Davies
Jul 30, 2005·The Journal of Organic Chemistry·Antonio ArcadiLuca M Parisi