PDBsum entry 3k9x

Hydrolase

PDB id: 3k9x

Contents

Protein chains

86 a.a. *

238 a.a. *

81 a.a. *

Ligands

GOL ×6

MBM ×2

Metals

_CA ×2

_NA ×2

Waters ×669

* Residue conservation analysis

PDB id:

3k9x

Name:

Hydrolase

Title:

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

Structure:

Protein (coagulation factor x). Chain: a, c. Fragment: egf-like domains (unp residues 85 to 178). Synonym: stuart factor, stuart-prower factor, factor x light chain, factor x heavy chain, activated factor xa heavy chain. Protein (coagulation factor x). Chain: b, d. Fragment: catalytic domains (unp residues 235 to 472). Synonym: stuart factor, stuart-prower factor, factor x light chain,

Source:

Homo sapiens. Human. Organism_taxid: 9606. Secretion: blood. Secretion: blood

Resolution:

1.90Å R-factor: 0.177 R-free: 0.240

Authors:

H.E.Klei,K.Kish,K.Ghosh,A.Rushith

Key ref:

Y.Shi et al. (2009). Aroylguanidine-based factor Xa inhibitors: the discovery of BMS-344577. Bioorg Med Chem Lett, 19, 6882-6889. PubMed id: 19896847

Date:

16-Oct-09 Release date: 15-Dec-09

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 86 a.a.

Protein chains

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 238 a.a.

Protein chain

P00742  (FA10_HUMAN) -  Coagulation factor X from Homo sapiens

Seq: 488 a.a.

Struc: 81 a.a.

Enzyme reactions

• Enzyme class: Chains A, B, C, D: E.C.3.4.21.6 - coagulation factor Xa.
• Reaction: Preferential cleavage: Arg-|-Thr and then Arg-|-Ile bonds in prothrombin to form thrombin.

Bioorg Med Chem Lett 19:6882-6889 (2009)

PubMed id: 19896847

Aroylguanidine-based factor Xa inhibitors: the discovery of BMS-344577.

Y.Shi, C.Li, S.P.O'Connor, J.Zhang, M.Shi, S.N.Bisaha, Y.Wang, D.Sitkoff, A.T.Pudzianowski, C.Huang, H.E.Klei, K.Kish, J.Yanchunas, E.C.Liu, K.S.Hartl, S.M.Seiler, T.E.Steinbacher, W.A.Schumacher, K.S.Atwal, P.D.Stein.

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.