Discovery of a novel 2-(1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole derivative as an EP 1 receptor antagonist and in vivo studies in a bone fracture model

We describe a medicinal chemistry approach to the discovery of a novel EP antagonist exhibiting high potency and good pharmacokinetics. Our starting point is 1, an EP receptor antagonist that exhibits pharmacological efficacy in cystometry models following intravenous administration. Despite its goo...

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Bibliographic Details
Published inBioorganic & medicinal chemistry letters Vol. 28; no. 14; pp. 2408 - 2412
Main Authors Atobe, Masakazu, Naganuma, Kenji, Kawanishi, Masashi, Hayashi, Takahiko, Suzuki, Hiroko, Nishida, Masahiro, Arai, Hirokazu
Format Journal Article
LanguageEnglish
Published England 01.08.2018
Subjects
Target validation
Prostaglandin E
Bone fracture healing
EP receptor
Oral administration
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Summary:We describe a medicinal chemistry approach to the discovery of a novel EP antagonist exhibiting high potency and good pharmacokinetics. Our starting point is 1, an EP receptor antagonist that exhibits pharmacological efficacy in cystometry models following intravenous administration. Despite its good potency in vitro, the high lipophilicity of 1 is a concern in long-term in vivo studies. Further medicinal chemistry efforts identified 4 as an improved lead compound with good in vitro ADME profile applicable to long term in vivo studies. A rat fracture study was conducted with 4 for 4 weeks to validate its utility in bone fracture healing. The results suggest that this EP receptor antagonist stimulates callus formation and thus 4 has potential for enhancing fracture healing.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2018.06.022