Synthesis and structure–activity relationship of potent, selective and orally active anthranilamide-based factor Xa inhibitors: Application of weakly basic sulfoximine group as novel S4 binding element

A novel series of potent and efficacious factor Xa inhibitors which possesses sulfoximine moiety as novel S4 binding element in anthranilamide chemotype has been identified. Lead optimization at this novel P4 group led to many potent factor Xa inhibitors with excellent anticoagulant activity in human plasma. Selected compounds were dosed orally in rats and checked for their ex vivo prothrombin time prolonging activity, which resulted in identification of compound 5-chloro-N-(5-chloropyridin-2-yl)-2-(4-(N-(2-(diethylamino)acetyl)-S-methylsulfonimidoyl)benzamido)benzamide (18f). The detailed pharmacokinetic evaluation and subsequent metabolism study of 18f suggested the presence of an active metabolite. The compound 18f and its active metabolite 18b demonstrated excellent in vivo efficacy in both arterial and venous thrombosis model in rats and were found to be highly selective against related serine proteases. Based on this promising profile, compound 18f was selected for further evaluation.

Graphical abstractA novel series (I) of potent and efficacious factor Xa inhibitors which possesses sulfoximine moiety as novel S4 binding element in anthranilamide chemotype has been identified.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Sulfoximine moiety as novel S4 binding element for factor Xa has been identified. ► SAR study enabled identification of compound 18f as potent FXa inhibitor. ► Metabolism study indicated presence of an active metabolite 18b generated from 18f. ► Compound 18f and its metabolite 18b displayed excellent in vivo efficacy in rats.