Structure-Based Design of Macrocyclic Coagulation Factor VIIa Inhibitors

Priestley, E. Scott; Cheney, Daniel L.; DeLucca, Indawati; Wei, Anzhi; Luettgen, Joseph M.; Rendina, Alan R.; Wong, Pancras C.; Wexler, Ruth R.

doi:10.1021/acs.jmedchem.5b00788

Structure-Based Design of Macrocyclic Coagulation Factor VIIa Inhibitors

Journal Article · Tue Jul 07 00:00:00 EDT 2015 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.5b00788· OSTI ID:1347770

Priestley, E. Scott ^[1]; Cheney, Daniel L. ^[1]; DeLucca, Indawati ^[1]; Wei, Anzhi ^[1]; Luettgen, Joseph M. ^[1]; Rendina, Alan R. ^[1]; Wong, Pancras C. ^[1]; Wexler, Ruth R. ^[1]

Bristol-Myers Squibb Research & Development, Pennington, NJ (United States)

On the basis of a crystal structure of a phenylpyrrolidine lead and subsequent molecular modeling results, we designed and synthesized a novel series of macrocyclic FVIIa inhibitors. Here, the optimal 16-membered macrocycle was 60-fold more potent than an acyclic analog. Further potency optimization by incorporation of P1' alkyl sulfone and P2 methyl groups provided a macrocycle with TF/FVIIa K_i = 1.6 nM, excellent selectivity against a panel of seven serine proteases, and FVII-deficient prothrombin time EC_2x = 1.2 μM. Discovery of this potent, selective macrocyclic scaffold opens new possibilities for the development of orally bioavailable FVIIa inhibitors.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE

OSTI ID:: 1347770

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 15 Vol. 58; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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peptides and proteins
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Structure-Based Design of Macrocyclic Coagulation Factor VIIa Inhibitors

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