Decreasing the rate of metabolic ketone reduction in the discovery of a clinical acetyl-CoA carboxylase inhibitor for the treatment of diabetes.
Decreasing the rate of metabolic ketone reduction in the discovery of a clinical acetyl-CoA carboxylase inhibitor for the treatment of diabetes.
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DOI：
10.1021/jm5016022
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发表时间：
2014-12-26
影响因子：
7.3
通讯作者：
Vajdos FF
中科院分区：
文献类型：
--
作者：
Griffith DA;Kung DW;Esler WP;Amor PA;Bagley SW;Beysen C;Carvajal-Gonzalez S;Doran SD;Limberakis C;Mathiowetz AM;McPherson K;Price DA;Ravussin E;Sonnenberg GE;Southers JA;Sweet LJ;Turner SM;Vajdos FF
乙酰辅酶A羧化酶（ACC）抑制剂为2型糖尿病（T2DM）、肝脂肪变性和癌症的治疗提供了显著的潜力。然而，在人体试验中鉴定适合于测试该假设的工具化合物一直具有挑战性。辉瑞公司最近报道的一系列含螺环酮的ACC抑制剂在体内通过酮还原代谢，这使人体药理学预测复杂化。我们公开了通过在酮羰基附近引入空间位阻可以大大减弱这种代谢还原。加入弱碱性官能团改善了溶解度，并导致9被鉴定为治疗T2DM的临床候选物。I期临床研究表明，暴露量呈剂量比例增加，单次给药可抑制新生脂肪生成（DNL），间接量热法的变化与全身脂肪酸氧化增加一致。这种靶点接合的证明验证了化合物9用于评估DNL在人类疾病中的作用的用途。
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.
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DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
Evans, P
通讯作者：
Evans, P
影响因子：
4.8
作者：
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影响因子：
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影响因子：
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作者：
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通讯作者：
Fukatsu, Kohji
影响因子：
1.8
作者：
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通讯作者：
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