The discovery of D1 subtype-selective agonists with drug-like properties has been an enduring challenge for the greater part of 40 years. All known D1-selective agonists are catecholamines that bring about receptor desensitization and undergo rapid metabolism, thus limiting their utility as a therapeutic for chronic illness such as schizophrenia and Parkinson’s disease. Our high-throughput screening efforts on D1 yielded a single non-catecholamine hit PF-4211 (6) that was developed into a series of potent D1 receptor agonist leads with high oral bioavailability and CNS penetration. An important structural feature of this series is the locked biaryl ring system resulting in atropisomerism. Disclosed herein is a summary of our hit-to-lead efforts on this series of D1 activators culminating in the discovery of atropisomer 31 (PF-06256142), a potent and selective orthosteric agonist of the D1 receptor that has reduced receptor desensitization relative to dopamine and other catechol-containing agonists.

中文翻译：

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减少脱敏的阻转异构体D1激动剂的发现和前导优化

具有药物样特性的D1亚型选择性激动剂的发现在40年来的大部分时间里一直是一个持久的挑战。所有已知的D1选择性激动剂都是儿茶酚胺，会引起受体脱敏并进行快速代谢，因此限制了它们作为慢性疾病如精神分裂症和帕金森氏病的治疗剂的用途。我们对D1进行的高通量筛选工作产生了单个非儿茶酚胺命中PF-4211（6）被开发为一系列有效的D1受体激动剂，具有较高的口服生物利用度和CNS渗透性。该系列的一个重要结构特征是锁定的联芳基环系统，导致阻转异构现象。本文公开了我们在这一系列D1激活剂上的领先研究成果的总结，最终发现了Atropisomer 31（PF-06256142），这是一种D1受体的强效选择性正构激动剂，相对于多巴胺，其脱敏性降低了和其他含有邻苯二酚的激动剂。