SAR and X-ray structures of enantiopure 1,2-cis-(1R,2S)-cyclopentyldiamine and cyclohexyldiamine derivatives as inhibitors of coagulation Factor Xa.

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Qiao JX, Chang CH, Cheney DL, Morin PE, Wang GZ, King SR, Wang TC, Rendina AR, Luettgen JM, Knabb RM, Wexler RR, Lam PY

SAR and X-ray structures of enantiopure 1,2-cis-(1R,2S)-cyclopentyldiamine and cyclohexyldiamine derivatives as inhibitors of coagulation Factor Xa.

Bioorg Med Chem Lett. 2007 Aug 15;17(16):4419-27. Epub 2007 Jun 10.

PubMed ID

17588746 [ View in PubMed

]

Abstract

In the search of Factor Xa (FXa) inhibitors structurally different from the pyrazole-based series, we identified a viable series of enantiopure cis-(1R,2S)-cycloalkyldiamine derivatives as potent and selective inhibitors of FXa. Among them, cyclohexyldiamide 7 and cyclopentyldiamide 9 were the most potent neutral compounds, and had good anticoagulant activity comparable to the pyrazole-based analogs. Crystal structures of 7-FXa and 9-FXa illustrate binding similarities and differences between the five- and the six-membered core systems, and provide rationales for the observed SAR of P1 and linker moieties.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
5-CHLORO-N-((1R,2S)-2-(4-(2-OXOPYRIDIN-1(2H)-YL)BENZAMIDO) CYCLOPENTYL)THIOPHENE-2-CARBOXAMIDE	Coagulation factor X	Ki (nM)	0.43	N/A	N/A	Details
5-CHLORO-N-(2-(4-(2-OXOPYRIDIN-1(2H)-YL)BENZAMIDO)ETHYL)THIOPHENE-2-CARBOXAMIDE	Coagulation factor X	Ki (nM)	1.5	N/A	N/A	Details
Apixaban	Coagulation factor X	Ki (nM)	0.08	N/A	N/A	Details