Discovery of a Highly Potent, Selective, and Orally Bioavailable Macrocyclic Inhibitor of Blood Coagulation Factor VIIa-Tissue Factor Complex.
Basic Information
ID: ALA3853316
Journal: J Med Chem
Title: Discovery of a Highly Potent, Selective, and Orally Bioavailable Macrocyclic Inhibitor of Blood Coagulation Factor VIIa-Tissue Factor Complex.
Authors: Zhang X, Glunz PW, Johnson JA, Jiang W, Jacutin-Porte S, Ladziata V, Zou Y, Phillips MS, Wurtz NR, Parkhurst B, Rendina AR, Harper TM, Cheney DL, Luettgen JM, Wong PC, Seiffert D, Wexler RR, Priestley ES.
Abstract: Inhibitors of the tissue factor (TF)/factor VIIa complex (TF-FVIIa) are promising novel anticoagulants which show excellent efficacy and minimal bleeding in preclinical models. Starting with an aminoisoquinoline P1-based macrocyclic inhibitor, optimization of the P' groups led to a series of highly potent and selective TF-FVIIa inhibitors which displayed poor permeability. Fluorination of the aminoisoquinoline reduced the basicity of the P1 group and significantly improved permeability. The resulting lead compound was highly potent, selective, and achieved good pharmacokinetics in dogs with oral dosing. Moreover, it demonstrated robust antithrombotic activity in a rabbit model of arterial thrombosis.
CiteXplore: 27455395
DOI: 10.1021/acs.jmedchem.6b00469
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