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

[1] Discovery of a novel phenylethyl benzamide glucokinase activator for the treatment of type 2 diabetes mellitus
Park, Kaapjoo
Lee, Byoung Moon
Kim, Young Hwan
Han, Taedong
Yi, Wonhui
Lee, Dong Hoon
Choi, Hyun Ho
Chong, Wonee
Lee, Chun Ho
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (02) : 537 - 542
[2] Glucokinase activators for the treatment of type 2 diabetes
Johnson, Theodore O.
Humphries, Paul S.
ANNUAL REPORTS IN MEDICINAL CHEMISTRY, VOL 41, 2006, 41 : 141 - 154
[3] Discovery of a liver selective glucokinase activator clinical development candidate for the treatment of Type 2 diabetes
Pfefferkorn, Jeffrey A.
Guzman-Perez, Angel
Litchfield, John
Aiello, Robert
Treadway, Judith L.
Pettersen, John
Minich, Martha L.
Filipski, Kevin J.
Jones, Christopher S.
Tu, Meihua
Aspnes, Gary
Risley, Hud
Wright, Stephen W.
Li, Jian-Cheng
Bian, Jianwei
Benbow, John
Dow, Robert L.
Bourassa, Patricia
D'Aquila, Theresa
Baker, Levenia
Barucci, Nicole
Robertson, Alan
Bourbonais, Francis
Derksen, David R.
MacDougall, Margit
VanVolkenburg, Maria
Cabrera, Over
Chen, Jing
Lapworth, Amanda Lee
Landro, James A.
Atkinson, Karen
Tan, Beijing
Yao, Lili
Kosa, Rachel E.
Haddish-Berhane, Nahor
Feng, Bo
Duignan, David B.
El-Kattan, Ayman
Berliner, Martin A.
Dunetz, Joshua R.
Murdande, Sharad
Liu, Shenping
Ammirati, Mark
Knafels, John
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2011, 241
[4] Identification and evaluation of a novel glucokinase allosteric activator in target cells and animal model of type 2 diabetes
Nagata, Y
Sasaki, K
Hosaka, H
Ooyama, S
Kadotani, A
Goto, H
Futamura, M
Nishimura, T
Iino, T
Bamba, M
Watanabe, H
Suzuki, J
Li, ZH
Moller, DE
Zhang, BB
Eiki, JI
DIABETES, 2004, 53 : A139 - A139
[5] Identification of small-molecule glucokinase activator for type-2-diabetes treatment: a structure-based virtual screening approach
Malini, Manokaran
Thilagavathi, Ramasamy
Vennila, Jannet
Malgija, Beutline
Praveena, Gandhi
Selvam, Chelliah
MOLECULAR SIMULATION, 2023, 49 (17) : 1596 - 1613
[6] Discovery of Piragliatin-First Glucokinase Activator Studied in Type 2 Diabetic Patients
Sarabu, Ramakanth
Bizzarro, Fred T.
Corbett, Wendy L.
Dvorozniak, Mark T.
Geng, Wanping
Grippo, Joseph F.
Haynes, Nancy-Ellen
Hutchings, Stanley
Garofalo, Lisa
Guertin, Kevin R.
Hilliard, Darryl W.
Kabat, Marek
Kester, Robert F.
Ka, Wang
Liang, Zhenmin
Mahaney, Paige E.
Marcus, Linda
Matschinsky, Franz M.
Moore, David
Racha, Jagdish
Radinov, Roumen
Ren, Yi
Qi, Lida
Pignatello, Michael
Spence, Cheryl L.
Steele, Thomas
Tengi, John
Grimsby, Joseph
JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (16) : 7021 - 7036
[7] Identification of YH-GKA, a novel benzamide glucokinase activator as therapeutic candidate for type 2 diabetes mellitus
Kaapjoo Park
Archives of Pharmacal Research, 2012, 35 : 2029 - 2033
[8] Identification of YH-GKA, a novel benzamide glucokinase activator as therapeutic candidate for type 2 diabetes mellitus
Park, Kaapjoo
ARCHIVES OF PHARMACAL RESEARCH, 2012, 35 (12) : 2029 - 2033
[9] Glucokinase Activators for the Potential Treatment of Type 2 Diabetes
Grimsby, J.
Berthel, S. J.
Sarabu, R.
CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2008, 8 (17) : 1524 - 1532
[10] Discovery of a potent glucokinase activator with a favorable liver and pancreas distribution pattern for the treatment of type 2 diabetes mellitus
Fujieda, Hiroki
Kogami, Masakazu
Sakairi, Masao
Kato, Noriyasu
Makino, Mitsuhiro
Takahashi, Naoki
Miyazawa, Toshiyuki
Harada, Satoko
Yamashita, Tokuyuki
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2018, 156 : 269 - 294

← 1 2 3 4 5 →