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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.
Nishimura, Yoshikazu; Esaki, Toru; Isshiki, Yoshiaki; Furuta, Yoshiyuki; Mizutani, Akemi; Kotake, Tomoya; Emura, Takashi; Watanabe, Yoshiaki; Ohta, Masateru; Nakagawa, Toshito; Ogawa, Kotaro; Arai, Shinichi; Noda, Hiroshi; Kitamura, Hidetomo; Shimizu, Masaru; Tamura, Tatsuya; Sato, Haruhiko.
Afiliação
  • Nishimura Y; Research Division, Chugai Pharmaceutical Co., Ltd., Komakado 1-135, Gotemba, Shizuoka 412-8513, Japan.
  • Esaki T; Research Division, Chugai Pharmaceutical Co., Ltd., Komakado 1-135, Gotemba, Shizuoka 412-8513, Japan.
  • Isshiki Y; Research Division, Chugai Pharmaceutical Co., Ltd., Komakado 1-135, Gotemba, Shizuoka 412-8513, Japan.
  • Furuta Y; Research Division, Chugai Pharmaceutical Co., Ltd., Komakado 1-135, Gotemba, Shizuoka 412-8513, Japan.
  • Mizutani A; Research Division, Chugai Pharmaceutical Co., Ltd., Komakado 1-135, Gotemba, Shizuoka 412-8513, Japan.
  • Kotake T; Research Division, Chugai Pharmaceutical Co., Ltd., Komakado 1-135, Gotemba, Shizuoka 412-8513, Japan.
  • Emura T; Research Division, Chugai Pharmaceutical Co., Ltd., Komakado 1-135, Gotemba, Shizuoka 412-8513, Japan.
  • Watanabe Y; Research Division, Chugai Pharmaceutical Co., Ltd., Komakado 1-135, Gotemba, Shizuoka 412-8513, Japan.
  • Ohta M; Research Division, Chugai Pharmaceutical Co., Ltd., Komakado 1-135, Gotemba, Shizuoka 412-8513, Japan.
  • Nakagawa T; Research Division, Chugai Pharmaceutical Co., Ltd., Komakado 1-135, Gotemba, Shizuoka 412-8513, Japan.
  • Ogawa K; Research Division, Chugai Pharmaceutical Co., Ltd., Komakado 1-135, Gotemba, Shizuoka 412-8513, Japan.
  • Arai S; Research Division, Chugai Pharmaceutical Co., Ltd., Komakado 1-135, Gotemba, Shizuoka 412-8513, Japan.
  • Noda H; Research Division, Chugai Pharmaceutical Co., Ltd., Komakado 1-135, Gotemba, Shizuoka 412-8513, Japan.
  • Kitamura H; Research Division, Chugai Pharmaceutical Co., Ltd., Komakado 1-135, Gotemba, Shizuoka 412-8513, Japan.
  • Shimizu M; Research Division, Chugai Pharmaceutical Co., Ltd., Komakado 1-135, Gotemba, Shizuoka 412-8513, Japan.
  • Tamura T; Research Division, Chugai Pharmaceutical Co., Ltd., Komakado 1-135, Gotemba, Shizuoka 412-8513, Japan.
  • Sato H; Research Division, Chugai Pharmaceutical Co., Ltd., Komakado 1-135, Gotemba, Shizuoka 412-8513, Japan.
J Med Chem ; 63(10): 5089-5099, 2020 05 28.
Article em En | MEDLINE | ID: mdl-32022560
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Compostos de Espiro / Receptor Tipo 1 de Hormônio Paratireóideo / Imidazolidinas Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Compostos de Espiro / Receptor Tipo 1 de Hormônio Paratireóideo / Imidazolidinas Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article