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Bioorg Med Chem Lett. 2016 Oct 15;26(20):5051-5057. doi: 10.1016/j.bmcl.2016.08.088. Epub 2016 Aug 28.

Synthesis and P1' SAR exploration of potent macrocyclic tissue factor-factor VIIa inhibitors.

Author information

1
Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, United States. Electronic address: vladimir.ladziata@bms.com.
2
Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, United States.

Abstract

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.

KEYWORDS:

Anticoagulant; Factor VIIa-TF inhibitor; Macrocycle; Thrombosis

PMID:
27612545
DOI:
10.1016/j.bmcl.2016.08.088
[Indexed for MEDLINE]

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