4x6m: Difference between revisions

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== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
Antithrombotic agents that are inhibitors of factor XIa (FXIa) have the potential to demonstrate robust efficacy with a low bleeding risk profile. Herein, we describe a series of tetrahydroquinoline (THQ) derivatives as FXIa inhibitors. Compound 1 was identified as a potent and selective tool compound for proof of concept studies. It exhibited excellent antithrombotic efficacy in rabbit thrombosis models and did not prolong bleeding times. This demonstrates proof of concept for the FXIa mechanism in animal models with a reversible, small molecule inhibitor.
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=6.7nM and modest oral exposure in dogs.


Tetrahydroquinoline Derivatives as Potent and Selective Factor XIa Inhibitors.,Quan ML, Wong PC, Wang C, Woerner F, Smallheer JM, Barbera FA, Bozarth JM, Brown RL, Harpel MR, Luettgen JM, Morin PE, Peterson T, Ramamurthy V, Rendina AR, Rossi KA, Watson CA, Wei A, Zhang G, Seiffert D, Wexler RR J Med Chem. 2014 Jan 17. PMID:24405333<ref>PMID:24405333</ref>
Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties.,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 Bioorg Med Chem Lett. 2015 Feb 4. pii: S0960-894X(15)00040-2. doi:, 10.1016/j.bmcl.2015.01.028. PMID:25728130<ref>PMID:25728130</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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