Identification of RO4597014, a Glucokinase Activator Studied in the Clinic for the Treatment of Type 2 Diabetes

被引：13

作者：

Qian, Yimin ^{[1
]}

Corbett, Wendy L. ^{[1
]}

Berthel, Steven J. ^{[1
]}

Choi, Duk Soon ^{[2
]}

Dvorozniak, Mark T. ^{[3
]}

Geng, Wanping ^{[4
]}

Gillespie, Paul ^{[1
]}

Guertin, Kevin R. ^{[1
]}

Haynes, Nancy-Ellen ^{[1
]}

Kester, Robert F. ^{[1
]}

Mennona, Francis A. ^{[1
]}

Moore, David ^{[4
]}

Racha, Jagdish ^{[4
]}

Radinov, Roumen ^{[5
]}

Sarabu, Ramakanth ^{[1
]}

Scott, Nathan R. ^{[1
]}

Grimsby, Joseph ^{[3
]}

Mallalieu, Navita L. ^{[6
]}

机构：

[1] Hoffmann La Roche Inc, Dept Discovery Chem, Nutley, NJ 07110 USA

[2] Hoffmann La Roche Inc, Dept Pharmaceut & Analyt Res, Nutley, NJ 07110 USA

[3] Hoffmann La Roche Inc, Dept Metab & Vasc Dis, Nutley, NJ 07110 USA

[4] Hoffmann La Roche Inc, Dept Drug Metab & Pharmacokinet, Nutley, NJ 07110 USA

[5] Hoffmann La Roche Inc, Dept Proc Res, Nutley, NJ 07110 USA

[6] Hoffmann La Roche Inc, Dept Clin Pharmacol, Nutley, NJ 07110 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2013年 / 4卷 / 04期

关键词：

Glucokinase activator; type; 2; diabetes; lipophilic ligand efficiency; metabolite; redox cycling; BENZAMIDE DERIVATIVES; DISCOVERY; DESIGN; CANDIDATE; EFFICACY; THERAPY; SAFETY; POTENT;

D O I：

10.1021/ml400027y

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

To resolve the metabolite redox cycling associated with our earlier clinical compound 2, we carried out lead optimization of lead molecule 1. Compound 4 showed improved lipophilic ligand efficiency and demonstrated robust glucose lowering in diet-induced obese mice without a liability in predictive preclinical drug safety studies. Thus, it was selected as a clinical candidate and further studied in type 2 diabetic patients. Clinical data suggests no evidence of metabolite cycling, which is consistent with the preclinical profiling of metabolism.

引用

页码：414 / 418

页数：5

共 50 条

[21] AZD1656, a novel glucokinase activator, lowers plasma glucose in patients with type 2 diabetes
Morrow, L.
Leonsson-Zachrisson, M.
Ericsson, H.
Wollbratt, M.
Knutsson, M.
Hompesch, M.
Norjavaara, E.
DIABETOLOGIA, 2011, 54 : S361 - S362
[22] Effects of Piragliatin, a Glucokinase Activator, on Fasting and Postprandial Plasma Glucose in Patients With Type 2 Diabetes Mellitus
Zhi, Jianguo
Zhai, Suoping
JOURNAL OF CLINICAL PHARMACOLOGY, 2016, 56 (02): : 231 - 238
[23] Chronic glucokinase activator treatment at clinically translatable exposures gives durable glucose lowering in two animal models of type 2 diabetes
Baker, D. J.
Wilkinson, G. P.
Atkinson, A. M.
Jones, H. B.
Coghlan, M.
Charles, A. D.
Leighton, B.
BRITISH JOURNAL OF PHARMACOLOGY, 2014, 171 (07) : 1642 - 1654
[24] Recent clinical advances of glucokinase activators in the treatment of diabetes mellitus type 2
Li, Wei
Zhang, Xiaoqing
Sun, Yan
Liu, Zhaohua
PHARMAZIE, 2020, 75 (06): : 230 - 235
[25] Liver selective glucokinase activation a new paradigm for treatment of type 2 diabetes
Valcarce, C.
Bodvarsdottir, T.
Wahl, P.
Larsen, M.
Fosgerau, K.
Blume, N.
Selmer, J.
Mjalli, A.
DIABETOLOGIA, 2008, 51 : S372 - S372
[26] A comprehensive review on glucokinase activators: Promising agents for the treatment of Type 2 diabetes
Thilagavathi, Ramasamy
Hosseini-Zare, Maryam Sadat
Malini, Manokaran
Selvam, Chelliah
CHEMICAL BIOLOGY & DRUG DESIGN, 2022, 99 (02) : 247 - 263
[27] Investigation of Functionally Liver Selective Glucokinase Activators for the Treatment of Type 2 Diabetes
Bebernitz, Gregory R.
Beaulieu, Valerie
Dale, Bethany A.
Deacon, Richard
Duttaroy, Alokesh
Gao, Jiaping
Grondine, Melissa S.
Gupta, Ramesh C.
Kakmak, Mesut
Kavana, Michael
Kirman, Louise C.
Liang, Jinsheng
Maniara, Wieslawa M.
Munshi, Siralee
Nadkarni, Sunil S.
Schuster, Herbert F.
Stams, Travis
Denny, Irene St.
Taslimi, Paul M.
Vash, Brian
Caplan, Shari L.
JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (19) : 6142 - 6152
[28] Structure-Based Drug Design: Identification of Glucokinase Activators from Natural Compounds for the Treatment of Type 2 Diabetes
Malini, Manokaran
Thilagavathi, Ramasamy
Singh, Sanjeev Kumar
Pravin, Arun
Selvam, Chelliah
CHEMISTRYSELECT, 2023, 8 (15):
[29] Glucokinase activator RO4389620 improves plasma glucose concentrations, beta-cell function, endogenous glucose output and glucose utilization in patients with type 2 diabetes
Bonadonna, Riccardo C.
Kapitza, Christoph
Heise, Tim
Avogaro, Angelo
Boldrin, Mark
Grimsby, Joseph
Mulligan, Mary E.
Zhi, Jianguo
Arbetengels, Christophe
Balena, Raffaella
DIABETES, 2008, 57 : A95 - A95
[30] Clinical validation of the dual-modes of action of glucokinase activator HMS5552 for type 2 diabetes
Chen, Li
Zhang, Yi
Jin, Xiaowei
Li, Yongguo
Leng, Yin
Li, Xuening
Gao, Xin
Li, Xiaoying
Zhu, Dalong
DIABETES-METABOLISM RESEARCH AND REVIEWS, 2014, 30 : 6 - 6

← 1 2 3 4 5 →