O'Mahony Gavin, Petersen Jens, Ek Margareta, Rae Rebecca, Johansson Carina, Jianming Liu, Prokoph Nina, Bergström Fredrik, Bamberg Krister, Giordanetto Fabrizio, Zarrouki Bader, Karlsson Daniel, Hogner Anders
Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden.
Mechanistic and Structural Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg 43183, Sweden.
ACS Med Chem Lett. 2022 Mar 11;13(4):681-686. doi: 10.1021/acsmedchemlett.1c00715. eCollection 2022 Apr 14.
Thiazolidinedione PPARγ agonists such as rosiglitazone and pioglitazone are effective antidiabetic drugs, but side effects have limited their use. It has been posited that their positive antidiabetic effects are mainly mediated by the inhibition of the CDK5-mediated Ser273 phosphorylation of PPARγ, whereas the side effects are linked to classical PPARγ agonism. Thus compounds that inhibit PPARγ Ser273 phosphorylation but lack classical PPARγ agonism have been sought as safer antidiabetic therapies. Herein we report the discovery by virtual screening of , which is a potent PPARγ binder and in vitro inhibitor of the CDK5-mediated phosphorylation of PPARγ Ser273 and displays negligible PPARγ agonism in a reporter gene assay. The pharmacokinetic properties of are compatible with oral dosing, enabling preclinical in vivo testing, and a 7 day treatment demonstrated an improvement in insulin sensitivity in the diabetic mouse model.
噻唑烷二酮类PPARγ激动剂，如罗格列酮和吡格列酮，是有效的抗糖尿病药物，但副作用限制了它们的使用。据推测，它们的积极抗糖尿病作用主要是通过抑制CDK5介导的PPARγ的Ser273磷酸化来实现的，而副作用则与经典的PPARγ激动作用有关。因此，人们一直在寻找能够抑制PPARγ Ser273磷酸化但缺乏经典PPARγ激动作用的化合物，作为更安全的抗糖尿病疗法。在此，我们报告通过虚拟筛选发现了一种化合物，它是一种有效的PPARγ结合剂，是CDK5介导的PPARγ Ser273磷酸化的体外抑制剂，并且在报告基因测定中显示出可忽略不计的PPARγ激动作用。该化合物的药代动力学性质与口服给药相容，能够进行临床前体内试验，并且为期7天的治疗证明在糖尿病小鼠模型中胰岛素敏感性有所改善。
