Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties.

Abstract:

:Compound 2 was previously identified as a potent inhibitor of factor XIa lacking oral bioavailability. A structure-based approach was used to design analogs of 2 with novel P1 moieties with good selectivity profiles and oral bioavailability. Further optimization of the P1 group led to the identification of a 4-chlorophenyltetrazole P1 analog, which when combined with further modifications to the linker and P2' group provided compound 32 with FXIa Ki=6.7 nM and modest oral exposure in dogs.

journal_name

Bioorg Med Chem Lett

authors

Pinto DJ,Smallheer JM,Corte JR,Austin EJ,Wang C,Fang T,Smith LM 2nd,Rossi KA,Rendina AR,Bozarth JM,Zhang G,Wei A,Ramamurthy V,Sheriff S,Myers JE Jr,Morin PE,Luettgen JM,Seiffert DA,Quan ML,Wexler RR

doi

10.1016/j.bmcl.2015.01.028

subject

Has Abstract

pub_date

2015-04-01 00:00:00

pages

1635-42

issue

7

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(15)00040-2

journal_volume

25

pub_type

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