Discovery of a novel 2-(1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole derivative as an EP1 receptor antagonist and in vivo studies in a bone fracture model

• Published in: Bioorganic & medicinal chemistry letters 2018-08, Vol.28 (14), p.2408-2412
• Main Authors: Atobe, Masakazu, Naganuma, Kenji, Kawanishi, Masashi, Hayashi, Takahiko, Suzuki, Hiroko, Nishida, Masahiro, Arai, Hirokazu
• Format: Article
• Language: English
• Subjects: Bone fracture healing; EP1 receptor; Oral administration; Prostaglandin E2; Target validation
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.06.022

[Display omitted] •The effort to reduce the lipophilicity led to improve the pharmacokinetics profile.•PK study of 4 showed good exposure for long-term in vivo studies.•The possibility of fracture healing has been showed in bone fracture model with 4. We describe a medicinal chemistry approach to the discovery of a novel EP1 antagonist exhibiting high potency and good pharmacokinetics. Our starting point is 1, an EP1 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 EP1 receptor antagonist stimulates callus formation and thus 4 has potential for enhancing fracture healing.