Identification of 3,4-dihydro-2H-thiochromene 1,1-dioxide derivatives with a phenoxyethylamine group as highly potent and selective α1D adrenoceptor antagonists

A series of phenoxyethylamine derivatives was designed and synthesized to discover potent and selective human alpha(1D) adrenoceptor (alpha(1D) adrenergic receptor; alpha(1D) AR) antagonists. Compound 7 was taken from our internal compound collection as an attractive starting point and exhibited moderate binding affinity for alp AR and high selectivity against alpha(1A)- and alpha(1B)-ARs. We focused on modifying the 2-methylsulfonylbenzyl group of 7 to discover novel compounds structurally distinct from other reported alpha(1)-AR antagonists containing the phenoxyethylamine motif. Study of structure activity relationship guided by a targeted ligand-lipophilicity efficiency score led to the discovery of a novel scaffold of 3,4-dihydro-2H-thiochromene 1,1-dioxide for selective alpha(1D)-AR antagonists. Further optimization studies resulted in the identification of (4S)-N-4-[2-(2,5-difluorophenoxy)ethy1]-N-6-methyl-3,4-dihydro-2H-thiochromene-4,6-diamine 1,1-dioxide, (S)-41, as a novel, highly potent and selective alpha(1D)-AR antagonist. Herein, we provide details of the structure activity relationship of the phenoxyethylamine analog for the potency and selectivity. (C) 2017 Elsevier Masson SAS. All rights reserved.