7T78

CRYSTAL STRUCTURE OF GLUCOKINASE (HEXOKINASE 4) COMPLEXED WITH LIGAND DIETHYL ({2-[3-(4-METHANESULFONYLPHENO XY)-5-{[(2S)-1-METHOXYPROPAN-2-YL]OXY}BENZAMIDO]-1,3-THIAZ OL-4-YL}METHYL)PHOSPHONATE

7T78 の概要

• エントリーDOI: 10.2210/pdb7t78/pdb
• 分子名称: Isoform 2 of Hexokinase-4, alpha-D-glucopyranose, SODIUM ION, ... (6 entities in total)
• 機能のキーワード: transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 106092.28

構造登録者

Muckelbauer, J.K. (登録日: 2021-12-14, 公開日: 2022-03-02, 最終更新日: 2024-02-28)

主引用文献

Shi, Y.,Wang, Y.,Meng, W.,Brigance, R.P.,Ryono, D.E.,Bolton, S.,Zhang, H.,Chen, S.,Smirk, R.,Tao, S.,Tino, J.A.,Williams, K.N.,Sulsky, R.,Nielsen, L.,Ellsworth, B.,Wong, M.K.Y.,Sun, J.H.,Leith, L.W.,Sun, D.,Wu, D.R.,Gupta, A.,Rampulla, R.,Mathur, A.,Chen, B.C.,Wang, A.,Fuentes-Catanio, H.G.,Kunselman, L.,Cap, M.,Zalaznick, J.,Ma, X.,Liu, H.,Taylor, J.R.,Zebo, R.,Jones, B.,Kalinowski, S.,Swartz, J.,Staal, A.,O'Malley, K.,Kopcho, L.,Muckelbauer, J.K.,Krystek Jr., S.R.,Spronk, S.A.,Marcinkeviciene, J.,Everlof, G.,Chen, X.Q.,Xu, C.,Li, Y.X.,Langish, R.A.,Yang, Y.,Wang, Q.,Behnia, K.,Fura, A.,Janovitz, E.B.,Pannacciulli, N.,Griffen, S.,Zinker, B.A.,Krupinski, J.,Kirby, M.,Whaley, J.,Zahler, R.,Barrish, J.C.,Robl, J.A.,Cheng, P.T.W.
Discovery of a Partial Glucokinase Activator Clinical Candidate: Diethyl ((3-(3-((5-(Azetidine-1-carbonyl)pyrazin-2-yl)oxy)-5-isopropoxybenzamido)-1 H -pyrazol-1-yl)methyl)phosphonate (BMS-820132).
J.Med.Chem., 65:4291-4317, 2022

PubMed Abstract: Glucokinase (GK) is a key regulator of glucose homeostasis, and its small-molecule activators represent a promising opportunity for the treatment of type 2 diabetes. Several GK activators have been advanced into clinical trials and have demonstrated promising efficacy; however, hypoglycemia represents a key risk for this mechanism. In an effort to mitigate this hypoglycemia risk while maintaining the efficacy of the GK mechanism, we have investigated a series of amino heteroaryl phosphonate benzamides as ''partial" GK activators. The structure-activity relationship studies starting from a "full GK activator" , which culminated in the discovery of the "partial GK activator" (BMS-820132), are discussed. The synthesis and and preclinical pharmacology profiles of and its pharmacokinetics (PK) are described. Based on its promising efficacy and preclinical ADME and safety profiles, was advanced into human clinical trials.

PubMed: 35179904
DOI: 10.1021/acs.jmedchem.1c02110

実験手法

X-RAY DIFFRACTION (2.4 Å)