Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist
| Autor: | Yoshiaki Watanabe, Haruhiko Sato, Hidetomo Kitamura, Tomoya Kotake, Yoshikazu Nishimura, Masaru Shimizu, Takashi Emura, Kotaro Ogawa, Toru Esaki, Toshito Nakagawa, Akemi Mizutani, Yoshiyuki Furuta, Shinichi Arai, Hiroshi Noda, Masateru Ohta, Tatsuya Tamura, Yoshiaki Isshiki |
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| Rok vydání: | 2020 |
| Předmět: |
Agonist
Hypoparathyroidism Swine medicine.drug_class Administration Oral Parathyroid hormone Pharmacology Imidazolidines Rats Sprague-Dawley chemistry.chemical_compound Oral administration Drug Discovery medicine Animals Humans Spiro Compounds Receptor Receptor Parathyroid Hormone Type 1 Sulfonyl chemistry.chemical_classification Rats chemistry Hormone receptor Microsome LLC-PK1 Cells Molecular Medicine Female Lead compound |
| Zdroj: | Journal of Medicinal Chemistry. 63:5089-5099 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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