Atobe Masakazu, Naganuma Kenji, Kawanishi Masashi, Hayashi Takahiko, Suzuki Hiroko, Nishida Masahiro, Arai Hirokazu
Laboratory for Medicinal Chemistry, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni, Shizuoka 410-221, Japan.
Laboratory for Medicinal Chemistry, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni, Shizuoka 410-221, Japan.
Bioorg Med Chem Lett. 2018 Aug 1;28(14):2408-2412. doi: 10.1016/j.bmcl.2018.06.022. Epub 2018 Jun 19.
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.
我们描述了一种用于发现具有高效能和良好药代动力学的新型EP拮抗剂的药物化学方法。我们的起始化合物是1，一种在静脉给药后的膀胱测压模型中表现出药理活性的EP受体拮抗剂。尽管其在体外具有良好的效能，但1的高亲脂性在长期体内研究中令人担忧。进一步的药物化学研究确定4是一种改进的先导化合物，具有适用于长期体内研究的良好体外ADME特性。用4对大鼠进行了为期4周的骨折研究，以验证其在骨折愈合中的效用。结果表明，这种EP受体拮抗剂可刺激骨痂形成，因此4具有促进骨折愈合的潜力。
