Download MendeleyCyanoguanidine-based lactam derivatives as a novel class of orally bioavailable factor Xa inhibitors.
Shi, Y., Zhang, J., Shi, M., O'Connor, S.P., Bisaha, S.N., Li, C., Sitkoff, D., Pudzianowski, A.T., Chong, S., Klei, H.E., Kish, K., Yanchunas, J., Liu, E.C., Hartl, K.S., Seiler, S.M., Steinbacher, T.E., Schumacher, W.A., Atwal, K.S., Stein, P.D.(2009) Bioorg Med Chem Lett 19: 4034-4041
- PubMed: 19541481
- DOI: https://doi.org/10.1016/j.bmcl.2009.06.014
- Primary Citation of Related Structures:
3HPT - PubMed 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.
Organizational Affiliation:
Research and Development, Bristol-Myers Squibb Company, PO Box 5400, Princeton, NJ 08543-5400, USA. yan.shi@bms.com
