Identification of 3,4-dihydro-2H-thiochromene 1,1-dioxide Derivatives with a Phenoxyethylamine Group As Highly Potent and Selective α Adrenoceptor Antagonists

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