Cyanoguanidine-based lactam derivatives as a novel class of orally bioavailable factor Xa inhibitors.
Basic Information
ID: ALA1152385
Journal: Bioorg Med Chem Lett
Title: Cyanoguanidine-based lactam derivatives as a novel class of orally bioavailable factor Xa inhibitors.
Authors: Shi Y, Zhang J, Shi M, O'Connor SP, Bisaha SN, Li C, Sitkoff D, Pudzianowski AT, Chong S, Klei HE, Kish K, Yanchunas J, Liu EC, Hartl KS, Seiler SM, Steinbacher TE, Schumacher WA, Atwal KS, Stein PD.
Abstract: The N,N'-disubstituted cyanoguanidine is an excellent bioisostere of the thiourea and ketene aminal functional groups. We report the design and synthesis of a novel class of cyanoguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The SAR studies led to the discovery of compound 4 (BMS-269223, K(i)=6.5nM, EC(2xPT)=32muM) as a selective, orally bioavailable FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models. The X-ray crystal structure of 4 bound in FXa is presented and key ligand-protein interactions are discussed.
CiteXplore: 19541481
DOI: 10.1016/j.bmcl.2009.06.014
Patent ID: ┄