Discovery of triazole-based uracil derivatives bearing amide moieties as novel dipeptidyl peptidase-IV inhibitors |
| |
| Institution: | 1. Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, PR China;2. Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China;3. Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China;1. Laboratory of Biochemistry and Enzymatic Engineering of Lipases, ENIS, Route of Soukra, P.O. Box 1173, 3038, University of Sfax, Tunisia;2. Laboratory of Applied Chemistry: Heterocycles, Lipids and Polymers, Faculty of Sciences of Sfax, University of Sfax, P.O. Box 802, 3000 Sfax, Tunisia;3. Electro-chemical Environmental Laboratory, ENIS, Route of Soukra, P.O. Box 1173, 3038, University of Sfax, Tunisia;1. School of Pharmacy, Health Science Center, Xi’an Jiaotong University, No. 76, Yanta West Road, Xi’an, Shaanxi, 710061, PR China;2. School of Science, Xi’an Jiaotong University, No. 28, Xianning West Road, Xi’an, Shaanxi, 710049, PR China;3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China;1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, PR China;2. School of Biological Science and Technology, University of Jinan, 336, Nan Xin Zhuang Xi Road, Jinan, Shandong 250022, PR China;3. School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100 Hai Quan Road, Fengxian Dictrict, Shanghai 201418, PR China;1. School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Airport Bypass Road, Gandhi Nagar, Bhopal, MP 462036, India;2. Department of Pharmacy, Indira Gandhi National Tribal University, Lalpur, Amarkantak, MP 484887, India;3. Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad 382481, Gujarat, India;4. Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, Madhya Pradesh 462066, India;1. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research—Ahmedabad, S. G. Highway, Thaltej, Ahmedabad 380054, Gujarat, India;2. Department of Pharmacology and Toxicology, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, S. G. Highway, Thaltej, Ahmedabad 380054, Gujarat, India;3. Department of Medicinal Chemistry, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, S. G. Highway, Thaltej, Ahmedabad 380054, Gujarat, India;1. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming 650201, People''s Republic of China;2. University of Chinese Academy of Sciences, Beijing 100049, People''s Republic of China |
| |
| Abstract: | Dipeptidyl peptidase-IV (DPP-4) is a validated target for T2DM treatment. We previously reported a novel series of triazole-based uracil derivatives bearing aliphatic carboxylic acids with potent DPP-4 inhibitory activities in vitro, but these compounds showed poor hypoglycemic effects in vivo. Herein we further optimized the triazole moiety by amidation of the carboxylic acid to improve in vivo activities. Two series of compounds 3a-f and 4a-g were designed and synthesized. By screening in DPP-4, compound 4c was identified as a potent DPP-4 inhibitor with the IC50 value of 28.62 nM. Docking study revealed compound 4c has a favorable binding mode and interpreted the SAR of these analogs. DPP-8 and DPP-9 tests indicated compound 4c had excellent selectivity over DPP-8 and DPP-9. Further in vivo evaluations revealed that compound 4c showed more potent hypoglycemic activity than its corresponding carboxylic acid in ICR mice and dose-dependently reduced glucose levels in type 2 diabetic C57BL/6 mice. The overall results have shown that compound 4c could be a promising lead for further development of novel DPP-4 agents treating T2DM. |
| |
| Keywords: | T2DM DPP-4 inhibitor Uracil derivatives Triazole Amide |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
