A series of phenoxyethylamine derivatives was designed and synthesized to discover potent and selective human α_1D adrenoceptor (α_1D adrenergic receptor; α_1D–AR) antagonists. Compound 7 was taken from our internal compound collection as an attractive starting point and exhibited moderate binding affinity for α_1D–AR and high selectivity against α_1A– and α_1B–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 α_1D–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 α_1D–AR antagonist. Herein, we provide details of the structure activity relationship of the phenoxyethylamine analog for the potency and selectivity.

一系列苯氧基乙基胺衍生物的设计和合成以发现有效的和选择性的人α _1D肾上腺素受体（α _1D肾上腺素能受体;α _1D -AR）拮抗剂。化合物7是从我们的内部化合物集合作为一个有吸引力的起点和表现出中度的结合亲和性为α _1D -AR和针对α高选择性_1A -和α _1B -ARs。我们集中在修改的2-甲基磺酰基苄基7来发现从其它报道的α结构上不同的新的化合物₁含有苯氧乙胺基序的–AR拮抗剂。通过有针对性的配体-亲油性效率引导结构活性关系研究得分导致3,4-二氢2的新型支架的发现ħ -thiochromene -1,1-二氧化物进行选择性α _1D -AR拮抗剂。进一步的优化研究确定了（4 S）-N ^4- [2-（2,5-二氟苯氧基）乙基] -N ^6-甲基-3,4-二氢-2 H-硫代色素-4,6-二胺1,1-dioxide（（S）– 41）作为一种新型的，高效且有选择性的_α1D–AR拮抗剂。在本文中，我们提供了有关苯氧基乙胺类似物的效价和选择性的结构活性关系的详细信息。