PDBsum entry 2p16

Hydrolase

PDB id: 2p16

Contents

Protein chains

234 a.a.

52 a.a.

Ligands

GG2

Metals

_CA

Waters ×121

References listed in PDB file

Key reference

• Title: Discovery of 1-(4-Methoxyphenyl)-7-Oxo-6-(4-(2-Oxopiperidin-1-Yl)phenyl)-4,5,6,7-Tetrahydro-1h-Pyrazolo[3,4-C]pyridine-3-Carboxamide (apixaban, Bms-562247), A highly potent, Selective, Efficacious, And orally bioavailable inhibitor of blood coagulation factor xa.
• Authors: D.J.Pinto, M.J.Orwat, S.Koch, K.A.Rossi, R.S.Alexander, A.Smallwood, P.C.Wong, A.R.Rendina, J.M.Luettgen, R.M.Knabb, K.He, B.Xin, R.R.Wexler, P.Y.Lam.
• Ref.: J Med Chem, 2007, 50, 5339-5356.
• PubMed id: 17914785

Abstract

Efforts to identify a suitable follow-on compound to razaxaban (compound 4) focused on modification of the carboxamido linker to eliminate potential in vivo hydrolysis to a primary aniline. Cyclization of the carboxamido linker to the novel bicyclic tetrahydropyrazolopyridinone scaffold retained the potent fXa binding activity. Exceptional potency of the series prompted an investigation of the neutral P1 moieties that resulted in the identification of the p-methoxyphenyl P1, which retained factor Xa binding affinity and good oral bioavailability. Further optimization of the C-3 pyrazole position and replacement of the terminal P4 ring with a neutral heterocycle culminated in the discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, compound 40). Compound 40 exhibits a high degree of fXa potency, selectivity, and efficacy and has an improved pharmacokinetic profile relative to 4.