DISCOVERY AND EVALUATION OF A SERIES OF 3-ACYLINDOLE IMIDAZOPYRIDINE PLATELET-ACTIVATING-FACTOR ANTAGONISTS

Studies conducted with the goal of discovering a second-generation pla telet-activating factor (PAF) antagonist have identified a novel class of potent and orally active antagonists which have high aqueous solub ility and long duration of action in animal models. The compounds aros e from the combination of the lipophilic indole portion of Abbott's fi rst-generation PAF antagonist ABT-299 (2) with the methylimidazopyridi ne heterocycle moiety of British Biotechnology's BB-882 (1) and posses s the positive attributes of both of these clinical candidates. Struct ure-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 ro-4-[(1H-2-methylimidazo[4,5-c]pyrid-1-yl)methyl] b enzoyl}indole hydrochloride (ABT-491, 22m.HCl) which has been evaluate d extensively and is currently in clinical development.