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 Lettjournal_title
Bioorganic & medicinal chemistry lettersauthors
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 RRdoi
10.1016/j.bmcl.2015.01.028subject
Has Abstractpub_date
2015-04-01 00:00:00pages
1635-42issue
7eissn
0960-894Xissn
1464-3405pii
S0960-894X(15)00040-2journal_volume
25pub_type
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