Exploration of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides as potent, orally active Factor Xa inhibitors with extended duration of action.

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Van Huis CA, Casimiro-Garcia A, Bigge CF, Cody WL, Dudley DA, Filipski KJ, Heemstra RJ, Kohrt JT, Leadley RJ Jr, Narasimhan LS, McClanahan T, Mochalkin I, Pamment M, Peterson JT, Sahasrabudhe V, Schaum RP, Edmunds JJ

Exploration of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides as potent, orally active Factor Xa inhibitors with extended duration of action.

Bioorg Med Chem. 2009 Mar 15;17(6):2501-11. doi: 10.1016/j.bmc.2009.01.063. Epub 2009 Feb 3.

PubMed ID

19231206 [ View in PubMed

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Abstract

Aiming to improve upon previously disclosed Factor Xa inhibitors, a series of 4,4-disubstituted pyrrolidine-1,2-dicarboxamides were explored with the intent of increasing the projected human half-life versus 5 (projected human t(1/2)=6 h). A stereospecific route to compounds containing a 4-aryl-4-hydroxypyrrolidine scaffold was developed, resulting in several compounds that demonstrated an increase in the half-life as well as an increase in the in vitro potency compared to 5. Reported herein is the discovery of 26, containing a (2R,4S)-4-hydroxy-4-(2,4-difluorophenyl)-pyrrolidine scaffold, which is a selective, orally bioavailable, efficacious Factor Xa inhibitor that appears suitable for a once-daily dosing (projected human t(1/2)=23 h).

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Eribaxaban	Coagulation factor X	IC 50 (nM)	0.57	N/A	N/A	Details