Indazole inhibitors of fructokinase (KHK) and methods of use in treating KHK-mediated disorders or diseases
申请人:REGENTS OF THE UNIVERSITY OF COLORADO, A BODY CORPORATE
公开号:US11083720B2
公开(公告)日:2021-08-10
Disclosed herein are novel indazole-based compounds that inhibit fructokinase (aka ketohexokinase) and the downstream metabolic effects mediated by fructose metabolism. Fructokinase inhibitors specifically block the metabolism of both dietary and endogenous fructose metabolism and have a host of potential metabolic benefits. These benefits including blocking sugar craving and sugar induced metabolic syndrome and diabetes, but also blocking fructose metabolism can benefit the rare orphan disease Hereditary Fructose Intolerance, obesity, insulin resistance, metabolic syndrome, fatty liver, hypertension, cardiac injury from ischemia, certain cancers (including hepatocellular and pancreas), acute kidney injury from ischemia, heat stress, rhabdomyolysis or radiocontrast, and chronic diabetic and nondiabetic renal disease.
本文公开的新型吲唑类化合物可抑制果糖激酶(又名酮己激酶)以及果糖代谢介导的下游代谢效应。果糖激酶抑制剂可特异性地阻断膳食果糖代谢和内源性果糖代谢,并具有一系列潜在的代谢益处。这些益处包括阻断对糖的渴望和糖诱发的代谢综合征和糖尿病,而且阻断果糖代谢还能使罕见的孤儿病遗传性果糖不耐受症、肥胖症、胰岛素抵抗、代谢综合征、脂肪肝、高血压、缺血引起的心脏损伤、某些癌症(包括肝细胞癌和胰腺癌)、缺血引起的急性肾损伤、热应激、横纹肌溶解症或放射性对比剂以及慢性糖尿病和非糖尿病肾病受益。