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Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-02-05 , DOI: 10.1021/acs.jmedchem.9b01743 Yoshikazu Nishimura 1 , Toru Esaki 1 , Yoshiaki Isshiki 1 , Yoshiyuki Furuta 1 , Akemi Mizutani 1 , Tomoya Kotake 1 , Takashi Emura 1 , Yoshiaki Watanabe 1 , Masateru Ohta 1 , Toshito Nakagawa 1 , Kotaro Ogawa 1 , Shinichi Arai 1 , Hiroshi Noda 1 , Hidetomo Kitamura 1 , Masaru Shimizu 1 , Tatsuya Tamura 1 , Haruhiko Sato 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-02-05 , DOI: 10.1021/acs.jmedchem.9b01743 Yoshikazu Nishimura 1 , Toru Esaki 1 , Yoshiaki Isshiki 1 , Yoshiyuki Furuta 1 , Akemi Mizutani 1 , Tomoya Kotake 1 , Takashi Emura 1 , Yoshiaki Watanabe 1 , Masateru Ohta 1 , Toshito Nakagawa 1 , Kotaro Ogawa 1 , Shinichi Arai 1 , Hiroshi Noda 1 , Hidetomo Kitamura 1 , Masaru Shimizu 1 , Tatsuya Tamura 1 , Haruhiko Sato 1
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We have previously shown that the oral administration of the small molecule hPTHR1 agonist PCO371 and its lead compound, 1 (CH5447240) results in PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. However, 1 was converted to a reactive metabolite in a human liver microsome assay. In this article, we report on the modification path that led to an enhancement of PTHR1 agonistic activity and reduction in the formation of a reactive metabolite to result in a potent, selective, and orally active PTHR1 agonist 1-(3,5-dimethyl-4-(2-((4-oxo-2-(4-(trifluoromethoxy)phenyl)-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-5,5-dimethylimidazolidine-2,4-dione (PCO371, 16c). This compound is currently being evaluated in a phase 1 clinical study for the treatment of hypoparathyroidism.
中文翻译：
铅优化和避免反应性代谢物导致PCO371，PCO371是一种有效，选择性和口服的人甲状旁腺激素受体1（hPTHR1）激动剂。
先前我们已经表明，小分子hPTHR1激动剂PCO371及其前导化合物1（CH5447240）的口服给药可在甲状旁腺切除的大鼠中产生类似PTH的降钙和降血脂活性。但是，在人肝微粒体测定中，1转化为反应性代谢产物。在本文中，我们报告了导致PTHR1激动剂活性增强和活性代谢产物形成减少的修饰途径，从而导致有效，选择性和口服的PTHR1激动剂1-（3,5-二甲基- 4-（2-（（4-氧代-2-（4-（三氟甲氧基）苯基）-1,3,8-三氮杂螺[4.5] dec-1-en-8-基）磺酰基）乙基）苯基）-5 1，5-二甲基咪唑烷-2，4-二酮（PCO371，16c）。该化合物目前正在1期临床研究中评估，用于治疗甲状旁腺功能减退。
更新日期：2020-02-05
中文翻译：
铅优化和避免反应性代谢物导致PCO371，PCO371是一种有效，选择性和口服的人甲状旁腺激素受体1（hPTHR1）激动剂。
先前我们已经表明，小分子hPTHR1激动剂PCO371及其前导化合物1（CH5447240）的口服给药可在甲状旁腺切除的大鼠中产生类似PTH的降钙和降血脂活性。但是，在人肝微粒体测定中，1转化为反应性代谢产物。在本文中，我们报告了导致PTHR1激动剂活性增强和活性代谢产物形成减少的修饰途径，从而导致有效，选择性和口服的PTHR1激动剂1-（3,5-二甲基- 4-（2-（（4-氧代-2-（4-（三氟甲氧基）苯基）-1,3,8-三氮杂螺[4.5] dec-1-en-8-基）磺酰基）乙基）苯基）-5 1，5-二甲基咪唑烷-2，4-二酮（PCO371，16c）。该化合物目前正在1期临床研究中评估，用于治疗甲状旁腺功能减退。
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