Design, synthesis and biological evaluation of renin inhibitors guided by simulated annealing of chemical potential simulations.

Autor: Cloudsdale IS; BioLeap, Inc., 6350 Quadrangle Drive, Suite 110, Chapel Hill, NC 27517, United States. Electronic address: isclou@gmail.com., Dickson JK Jr; BioLeap, Inc., 6350 Quadrangle Drive, Suite 110, Chapel Hill, NC 27517, United States., Barta TE; BioLeap, Inc., 6350 Quadrangle Drive, Suite 110, Chapel Hill, NC 27517, United States., Grella BS; BioLeap, Inc., 6350 Quadrangle Drive, Suite 110, Chapel Hill, NC 27517, United States., Smith ED; BioLeap, Inc., 6350 Quadrangle Drive, Suite 110, Chapel Hill, NC 27517, United States., Kulp JL 3rd; BioLeap, Inc., 6350 Quadrangle Drive, Suite 110, Chapel Hill, NC 27517, United States; Conifer Point Pharmaceuticals, 3805 Old Easton Road, Doylestown, PA 18902, United States., Guarnieri F; BioLeap, Inc., 6350 Quadrangle Drive, Suite 110, Chapel Hill, NC 27517, United States; Conifer Point Pharmaceuticals, 3805 Old Easton Road, Doylestown, PA 18902, United States., Kulp JL Jr; BioLeap, Inc., 6350 Quadrangle Drive, Suite 110, Chapel Hill, NC 27517, United States; Conifer Point Pharmaceuticals, 3805 Old Easton Road, Doylestown, PA 18902, United States. Electronic address: jlkjr@pobox.com.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2017 Aug 01; Vol. 25 (15), pp. 3947-3963. Date of Electronic Publication: 2017 May 19.
DOI: 10.1016/j.bmc.2017.05.032
Abstrakt: We have applied simulated annealing of chemical potential (SACP) to a diverse set of ∼150 very small molecules to provide insights into new interactions in the binding pocket of human renin, a historically difficult target for which to find low molecular weight (MW) inhibitors with good bioavailability. In one of its many uses in drug discovery, SACP provides an efficient, thermodynamically principled method of ranking chemotype replacements for scaffold hopping and manipulating physicochemical characteristics for drug development. We introduce the use of Constrained Fragment Analysis (CFA) to construct and analyze ligands composed of linking those fragments with predicted high affinity. This technique addresses the issue of effectively linking fragments together and provides a predictive mechanism to rank order prospective inhibitors for synthesis. The application of these techniques to the identification of novel inhibitors of human renin is described. Synthesis of a limited set of designed compounds provided potent, low MW analogs (IC 50 s<100nM) with good oral bioavailability (F>20-58%).
(Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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