Discovery of a novel 2-(1 H -pyrazolo[3,4- b ]pyridin-1-yl)thiazole derivative as an EP 1 receptor antagonist and in vivo studies in a bone fracture model
| Autor: | Masakazu Atobe, Kenji Naganuma, Takahiko Hayashi, Masashi Kawanishi, Hirokazu Arai, Hiroko Suzuki, Masahiro Nishida |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Callus formation medicine.drug_class Clinical Biochemistry Pharmaceutical Science Bone healing Pharmacology 01 natural sciences Biochemistry 03 medical and health sciences In vivo Drug Discovery medicine Molecular Biology ADME 010405 organic chemistry Chemistry Organic Chemistry Antagonist Bone fracture medicine.disease Receptor antagonist In vitro 0104 chemical sciences 030104 developmental biology Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry Letters. 28:2408-2412 |
| ISSN: | 0960-894X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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