Griffith David A, Kung Daniel W, Esler William P, Amor Paul A, Bagley Scott W, Beysen Carine, Carvajal-Gonzalez Santos, Doran Shawn D, Limberakis Chris, Mathiowetz Alan M, McPherson Kirk, Price David A, Ravussin Eric, Sonnenberg Gabriele E, Southers James A, Sweet Laurel J, Turner Scott M, Vajdos Felix F
Worldwide Medicinal Chemistry, ‡Cardiovascular, Metabolic and Endocrine Diseases Research Unit, and ∥Clinical Research Statistics, Pfizer Worldwide Research and Development , Cambridge, Massachusetts 02139, United States.
J Med Chem. 2014 Dec 26;57(24):10512-26. doi: 10.1021/jm5016022. Epub 2014 Dec 11.
Acetyl-CoA carboxylase (ACC) inhibitors offer significant potential for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis, and cancer. However, the identification of tool compounds suitable to test the hypothesis in human trials has been challenging. An advanced series of spirocyclic ketone-containing ACC inhibitors recently reported by Pfizer were metabolized in vivo by ketone reduction, which complicated human pharmacology projections. We disclose that this metabolic reduction can be greatly attenuated through introduction of steric hindrance adjacent to the ketone carbonyl. Incorporation of weakly basic functionality improved solubility and led to the identification of 9 as a clinical candidate for the treatment of T2DM. Phase I clinical studies demonstrated dose-proportional increases in exposure, single-dose inhibition of de novo lipogenesis (DNL), and changes in indirect calorimetry consistent with increased whole-body fatty acid oxidation. This demonstration of target engagement validates the use of compound 9 to evaluate the role of DNL in human disease.
乙酰辅酶A羧化酶（ACC）抑制剂在治疗2型糖尿病（T2DM）、肝脂肪变性和癌症方面具有巨大潜力。然而，找到适合在人体试验中验证这一假说的工具化合物颇具挑战性。辉瑞公司最近报道的一系列先进的含螺环酮ACC抑制剂在体内会通过酮还原进行代谢，这使得人体药理学预测变得复杂。我们发现，通过在酮羰基附近引入空间位阻，这种代谢还原作用可大大减弱。引入弱碱性官能团提高了溶解度，并确定化合物9为治疗T2DM的临床候选药物。I期临床研究表明，药物暴露量随剂量成比例增加，单次给药可抑制从头脂肪生成（DNL），间接测热法的变化与全身脂肪酸氧化增加一致。这种靶点参与的证明验证了使用化合物9来评估DNL在人类疾病中的作用。
