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

Journal Article · Sat Oct 01 00:00:00 EDT 2016 · Bioorganic & Medicinal Chemistry Letters

DOI:https://doi.org/10.1016/j.bmcl.2016.08.088· OSTI ID:1330868

Ladziata, Vladimir (Uladzimir); Glunz, Peter W.; Zou, Yan; Zhang, Xiaojun; Jiang, Wen; Jacutin-Porte, Swanee; Cheney, Daniel L.; Wei, Anzhi; Luettgen, Joseph M.; Harper, Timothy M.; Wong, Pancras C.; Seiffert, Dietmar; Wexler, Ruth R.; Priestley, E. Scott

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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1330868
• Journal Information: Bioorganic & Medicinal Chemistry Letters, Journal Name: Bioorganic & Medicinal Chemistry Letters Journal Issue: 20 Vol. 26; ISSN 0960-894X
• Country of Publication: United States
• Language: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES