3K9X

X-ray crystal structure of human fxa in complex with (S)-N-((2-METHYLBENZOFURAN-5-YLAMINO)(2-OXO-1-(2-OXO-2- (PYRROLIDIN-1-YL)ETHYL)AZEPAN-3- YLAMINO)METHYLENE)NICOTINAMIDE

Summary for 3K9X

• Entry DOI: 10.2210/pdb3k9x/pdb
• Related: 3ECN
• Descriptor: PROTEIN (Coagulation factor X), GLYCEROL, N-{N'-(2-methyl-1-benzofuran-5-yl)-N-[(3S)-2-oxo-1-(2-oxo-2-pyrrolidin-1-ylethyl)azepan-3-yl]carbamimidoyl}pyridine-3-carboxamide, ... (7 entities in total)
• Functional Keywords: serine protease, hydrolase, epidermal growth factor like domain, blood coagulation factor, cleavage on pair of basic residues, egf-like domain, gamma-carboxyglutamic acid, glycoprotein, hydroxylation, zymogen, blood clotting, blood coagulation, disulfide bond, protease, secreted
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P00742 P00742
• Total number of polymer chains: 4
• Total formula weight: 75881.82

Authors

Klei, H.E.,Kish, K.,Ghosh, K.,Rushith, A. (deposition date: 2009-10-16, release date: 2009-12-15, Last modification date: 2024-10-16)

Primary citation

Shi, Y.,Li, C.,O'Connor, S.P.,Zhang, J.,Shi, M.,Bisaha, S.N.,Wang, Y.,Sitkoff, D.,Pudzianowski, A.T.,Huang, C.,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.
Aroylguanidine-based factor Xa inhibitors: the discovery of BMS-344577
Bioorg.Med.Chem.Lett., 19:6882-6889, 2009

PubMed Abstract: We report the design and synthesis of a novel class of N,N'-disubstituted aroylguanidine-based lactam derivatives as potent and orally active FXa inhibitors. The structure-activity relationships (SAR) investigation led to the discovery of the nicotinoyl guanidine 22 as a potent FXa inhibitor (FXa IC(50)=4 nM, EC(2xPT)=7 microM). However, the potent CYP3A4 inhibition activity (IC(50)=0.3 microM) of 22 precluded its further development. Detailed analysis of the X-ray crystal structure of compound 22 bound to FXa indicated that the substituent at the 6-position of the nicotinoyl group of 22 would be solvent-exposed, suggesting that efforts to attenuate the unwanted CYP activity could focus at this position without affecting FXa potency significantly. Further SAR studies on the 6-substituted nicotinoyl guanidines resulted in the discovery of 6-(dimethylcarbamoyl) nicotinoyl guanidine 36 (BMS-344577, IC(50)=9 nM, EC(2xPT)=2.5 microM), which was found to be a selective, orally efficacious FXa inhibitor with an excellent in vitro liability profile, favorable pharmacokinetics and pharmacodynamics in animal models.

PubMed: 19896847
DOI: 10.1016/j.bmcl.2009.10.084

Experimental method

X-RAY DIFFRACTION (1.9 Å)