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JOURNAL ARTICLE
RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
Synthesis and P1' SAR exploration of potent macrocyclic tissue factor-factor VIIa inhibitors.
Bioorganic & Medicinal Chemistry Letters 2016 October 16
Selective tissue factor-factor VIIa complex (TF-FVIIa) inhibitors are viewed as promising compounds for treating thrombotic disease. In this contribution, we describe multifaceted exploratory SAR studies of S1'-binding moieties within a macrocyclic chemotype aimed at replacing cyclopropyl sulfone P1' group. Over the course of the optimization efforts, the 1-(1H-tetrazol-5-yl)cyclopropane P1' substituent emerged as an improved alternative, offering increased metabolic stability and lower clearance, while maintaining excellent potency and selectivity.
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