Discovery of renin inhibitors containing a simple aspartate binding moiety that imparts reduced P450 inhibition.

Autor: Lawhorn BG; Heart Failure DPU, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA. Electronic address: brian.2.lawhorn@gsk.com., Tran T; Heart Failure DPU, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA., Hong VS; Heart Failure DPU, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA., Morgan LA; Heart Failure DPU, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA., Le BT; Heart Failure DPU, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA., Harpel MR; Heart Failure DPU, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA., Jolivette L; Heart Failure DPU, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA., Diaz E; Platform Sciences and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA., Schwartz B; Platform Sciences and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA., Gross JW; Platform Sciences and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA., Tomaszek T; Platform Sciences and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA., Semus S; Platform Sciences and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA., Concha N; Platform Sciences and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA., Smallwood A; Platform Sciences and Technology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA., Holt DA; Heart Failure DPU, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA., Kallander LS; Heart Failure DPU, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2017 Nov 01; Vol. 27 (21), pp. 4838-4843. Date of Electronic Publication: 2017 Sep 23.
DOI: 10.1016/j.bmcl.2017.09.046
Abstrakt: Discovery of potent renin inhibitors which contain a simplified alkylamino Asp-binding group and exhibit improved selectivity for renin over Cyp3A4 is described. Structure-function results in this series are rationalized based on analysis of selected compounds bound to renin, and the contribution of each molecular feature leading to the reduced P450 inhibition is quantified.
(Copyright © 2017 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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