Selective and dual action orally active inhibitors of thrombin and factor Xa.

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Young RJ, Brown D, Burns-Kurtis CL, Chan C, Convery MA, Hubbard JA, Kelly HA, Pateman AJ, Patikis A, Senger S, Shah GP, Toomey JR, Watson NS, Zhou P

Selective and dual action orally active inhibitors of thrombin and factor Xa.

Bioorg Med Chem Lett. 2007 May 15;17(10):2927-30. Epub 2007 Mar 30.

PubMed ID

17420122 [ View in PubMed

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Abstract

The synthetic entry to new classes of dual fXa/thrombin and selective thrombin inhibitors with significant oral bioavailability is described. This was achieved through minor modifications to the sulfonamide group in our potent and selective fXa inhibitor (E)-2-(5-chlorothien-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-(morpholin-4-yl)-2-oxoethyl ]-2-oxopyrrolidin-3-yl}ethenesulfonamide and these observed activity changes have been rationalised using structural studies.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
(2R)-2-(5-CHLORO-2-THIENYL)-N-{(3S)-1-[(1S)-1-METHYL-2-MORPHOLIN-4-YL-2-OXOETHYL]-2-OXOPYRROLIDIN-3-YL}PROPENE-1-SULFONAMIDE	Coagulation factor X	Ki (nM)	2	N/A	N/A	Details
(2R)-2-(5-CHLORO-2-THIENYL)-N-{(3S)-1-[(1S)-1-METHYL-2-MORPHOLIN-4-YL-2-OXOETHYL]-2-OXOPYRROLIDIN-3-YL}PROPENE-1-SULFONAMIDE	Prothrombin	Ki (nM)	2	N/A	N/A	Details
2-(5-CHLORO-2-THIENYL)-N-{(3S)-1-[(1S)-1-METHYL-2-MORPHOLIN-4-YL-2-OXOETHYL]-2-OXOPYRROLIDIN-3-YL}ETHANESULFONAMIDE	Coagulation factor X	Ki (nM)	154	N/A	N/A	Details
2-(5-CHLORO-2-THIENYL)-N-{(3S)-1-[(1S)-1-METHYL-2-MORPHOLIN-4-YL-2-OXOETHYL]-2-OXOPYRROLIDIN-3-YL}ETHANESULFONAMIDE	Prothrombin	Ki (nM)	17	N/A	N/A	Details
GW-813893	Coagulation factor X	Ki (nM)	4	N/A	N/A	Details
GW-813893	Prothrombin	Ki (nM)	367	N/A	N/A	Details