Add time:08/30/2019         Source:sciencedirect.com

A series of phenoxyethylamine derivatives was designed and synthesized to discover potent and selective human α1D adrenoceptor (α1D adrenergic receptor; α1D–AR) antagonists. Compound 7 was taken from our internal compound collection as an attractive starting point and exhibited moderate binding affinity for α1D–AR and high selectivity against α1A– and α1B–ARs. We focused on modifying the 2-methylsulfonylbenzyl group of 7 to discover novel compounds structurally distinct from other reported α1–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 α1D–AR antagonists. Further optimization studies resulted in the identification of (4S)-N4-[2-(2,5-difluorophenoxy)ethyl]-N6-methyl-3,4-dihydro-2H-thiochromene-4,6-diamine 1,1-dioxide, (S)–41, as a novel, highly potent and selective α1D–AR antagonist. Herein, we provide details of the structure activity relationship of the phenoxyethylamine analog for the potency and selectivity.

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