Optimization of spirocyclic proline tryptophan hydroxylase-1 inhibitors

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• 作者：Daniel R. Goldberg^a ; ^{dgoldberg@kineta.us} ; Sté ; phane De Lombaert^a ; Robert Aiello^a ; Patricia Bourassa^a ; Nicole Barucci^a ; Qing Zhang^a ; Vishwas Paralkar^a ; Adam J. Stein^b ; Melissa Holt^b ; Jim Valentine^a ; William Zavadoski^a
• 关键词：Tryptophan hydroxylase-1 ; Serotonin ; TPH-1 ; 5-HT
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：27
• 期：3
• 页码：413-419
• 全文大小：3126 K
• 卷排序：27

文摘

As a follow-up to the discovery of our spirocyclic proline-based TPH1 inhibitor lead, we describe the optimization of this scaffold. Through a combination of X-ray co-crystal structure guided design and an in vivo screen, new substitutions in the lipophilic region of the inhibitors were identified. This effort led to new TPH1 inhibitors with in vivo efficacy when dosed as their corresponding ethyl ester prodrugs. In particular, 15b (KAR5585), the prodrug of the potent TPH1 inhibitor 15a (KAR5417), showed robust reduction of intestinal serotonin (5-HT) levels in mice. Furthermore, oral administration of 15b generated high and sustained systemic exposure of the active parent 15a in rats and dogs. KAR5585 was selected for further pharmacological evaluation in disease models associated with a dysfunctional peripheral 5-HT system.