2006

Multi-membered N-heterocyclesR 0690 Ketene Aminal-Based Lactam Derivatives as a Novel Class of Orally Active FXa

Inhibitors. — Replacement of the thiourea group of a human FXa inhibitor lead with a 2-nitroketene aminal, as well as substitution of the aromatic portion by a methylben-zofuranyl function provides a more potent compound. To further explore the struc-ture—activity relationship of ketene substituents, additional compounds based on the methylbenzofuranyl function as the S1 pharmacophore are synthesized [cf. (VII)]. The members of this class exhibit potent and highly selective anti-FXa activity. The meth-ylbenzofuranyl molecule turns out to be the critical S1 binding element, and the ketene aminals are good bioisosteres for the thiourea functional group. — (SHI*, Y.; et al.; Bioorg. Med. Chem. Lett. 15 (2005) 24, 5453-5458; Bristol-Myers Squibb Pharm. Res. Inst., Princeton, NJ 08543, USA; Eng.) — H. Hoennerscheid

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