title: Design, synthesis, and pharmacological evaluation of benzamide derivatives as glucokinase activators.
abstract: A series of benzamide derivatives were assembled by using the privileged-fragment-merging (PFM) strategy and their SAR studies as glucokinase activators were described. Compounds 5 and 16b were identified having a suitable balance of potency and activation profile. They showed EC(50) values of 28.3 and 44.8 nM, and activation folds of 2.4 and 2.2, respectively. However, both compounds displayed a minor reduction in plasma glucose levels on imprinting control region (ICR) mice. Unfavorable pharmacokinetic profiles (PK) were also observed on these two compounds.
authors.affiliation: Synthetic Organic and Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Mao
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Ning
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Liu
authors.forename: Qingzhang
authors.initials: Q
authors.lastname: Zhu
authors.forename: Ying
authors.initials: Y
authors.lastname: Leng
authors.forename: Ao
authors.initials: A
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001549:Benzamides / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D005941:Glucokinase / Q000737:chemistry / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C574180:(S)-3-(4-((3-fluoropyrrolidin-1-yl)sulfonyl)phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)-N-(thiazol-2-yl)benzamide; C574179:3-(4-(cyclopropylsulfonyl)phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)-N-(thiazol-2-yl)benzamide; D001549:Benzamides; D007004:Hypoglycemic Agents; D013844:Thiazoles; C037689:benzamide; D005941:Glucokinase