By use of parallel chemistry coupled with physicochemical property design, a series of selective κ opioid antagonists have been discovered. The parallel chemistry strategy utilized key monomer building blocks to rapidly expand the desired SAR space. The potency and selectivity of the in vitro κ antagonism were confirmed in the tail-flick analgesia model. This model was used to build an exposure–response relationship between the κ K_i and the free brain drug levels. This strategy identified 2-methyl-N-((2′-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine, PF-4455242, which entered phase 1 clinical testing and has demonstrated target engagement in healthy volunteers.

中文翻译：

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选择性小分子κ阿片类拮抗剂（2-甲基-N -（（（2'-（吡咯烷基-1-基磺酰基）联苯-4-基）甲基）丙-1-胺，PF-4455242）的设计和发现

通过使用平行化学结合物理化学性质设计，发现了一系列选择性κ阿片拮抗剂。平行化学策略利用关键的单体构建基块来快速扩展所需的SAR空间。在甩尾镇痛模型中证实了体外κ拮抗作用的效力和选择性。该模型被用来建立κ之间的暴露-反应关系ķ_我和无脑的药物水平。该策略确定了2-甲基-N -（（（2'-（吡咯烷基-1-基磺酰基）联苯-4-基）甲基）丙-1-胺PF-4455242，该药物已进入1期临床试验，并已证明具有靶标靶点在健康的志愿者中。