Johnson James A, Tora George, Pi Zulan, Phillips Monique, Yin Xiaohong, Yang Richard, Zhao Lei, Chen Alice Y, Taylor David S, Basso Michael, Rose Anne, Behnia Kamelia, Onorato Joelle, Chen Xue-Qing, Abell Lynn M, Lu Hao, Locke Gregory, Caporuscio Christian, Galella Michael, Adam Leonard P, Gordon David, Wexler Ruth R, Finlay Heather J
Departments of Discovery Chemistry, Biology, Pharmaceutics, Mechanistic Biochemistry, Preclinical Candidate Optimization, Bioanalytical Research, and Crystallography, Bristol-Myers Squibb, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
ACS Med Chem Lett. 2018 Nov 21;9(12):1263-1268. doi: 10.1021/acsmedchemlett.8b00424. eCollection 2018 Dec 13.
Endothelial lipase (EL) selectively metabolizes high density lipoprotein (HDL) particles. Inhibition of EL has been shown to increase HDL concentration in preclinical animal models and was targeted as a potential treatment of atherosclerosis. We describe the introduction of an α-sulfone moiety to a benzothiazole series of EL inhibitors resulting in increased potency versus EL. Optimization for selectivity versus hepatic lipase and pharmacokinetic properties resulted in the discovery of , which showed good in vitro potency and bioavailability but, unexpectedly, did not increase HDL in the mouse pharmacodynamic model at the target plasma exposure.
内皮脂肪酶（EL）可选择性地代谢高密度脂蛋白（HDL）颗粒。在临床前动物模型中，抑制EL已被证明可提高HDL浓度，因此它被作为动脉粥样硬化的一种潜在治疗靶点。我们描述了在苯并噻唑系列EL抑制剂中引入α-砜部分，从而提高了对EL的抑制效力。通过优化对肝脂肪酶的选择性和药代动力学性质，发现了[具体化合物名称未给出]，它在体外表现出良好的效力和生物利用度，但出乎意料的是，在小鼠药效学模型中，在达到目标血浆暴露水平时并未提高HDL水平。
