Selective agonism of dopamine D1 receptors has been a therapeutic goal for neurological and psychiatric disorders such as Parkinson’s and Schizophrenia for nearly 40 years. There have been a number of advancements in understanding the D1R orthosteric binding site and GPCR signaling cascades, but until recently, leads with good oral pharmacokinetics have remained elusive primarily due to the pharmacokinetic challenges presented by the catechol functionality found in the majority of D1-selective chemical matter. Here we disclose the discovery and optimization of a novel series of orally bioavailable, CNS penetrant, non-catechol D1 selective orthosteric agonists. Lead examples from this series exist as stable atropisomers due to a hindered biaryl bond. In addition, these ligands display evidence of distinct binding to the D1R orthosteric site that leads to significantly reduced desensitization and recruitment of b-arrestin. Compounds from this series were developed and advanced into clinical studies.

Discovery of orally bioavailable non-catechol atropisomer dopamine D1 agonists with reduced desensitization

256th National Meeting (2018)

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