Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 2. Leveraging Structure-Based Drug Design to Identify Analogues with Improved Pharmacokinetic Profiles

被引：22

作者：

St Jean, David J., Jr. ^{[1
]}

Ashton, Kate S. ^{[1
]}

Bartberger, Michael D. ^{[2
]}

Chen, Jie ^{[4
]}

Chmait, Samer ^{[2
]}

Cupples, Rod ^{[3
]}

Galbreath, Elizabeth ^{[5
]}

Helmering, Joan ^{[3
]}

Hong, Fang-Tsao ^{[1
]}

Jordan, Steven R. ^{[2
]}

Liu, Longbin ^{[1
]}

Kunz, Roxanne K. ^{[1
]}

Michelsen, Klaus ^{[2
]}

Nishimura, Nobuko ^{[1
]}

Pennington, Lewis D. ^{[1
]}

Poon, Steve F. ^{[1
]}

Reid, Darren ^{[6
]}

Sivits, Glenn ^{[3
]}

Stec, Markian M. ^{[1
]}

Tadesse, Seifu ^{[1
]}

Tamayo, Nuria ^{[1
]}

Van, Gwyneth ^{[5
]}

Yang, Kevin C. ^{[1
]}

Zhang, Jiandong ^{[2
]}

Norman, Mark H. ^{[1
]}

Fotsch, Christopher ^{[1
]}

Lloyd, David J. ^{[3
]}

Hale, Clarence ^{[3
]}

机构：

[1] Amgen Inc, Dept Therapeut Discovery Med Chem, Thousand Oaks, CA 91320 USA

[2] Amgen Inc, Dept Therapeut Discovery Mol Struct & Characteriz, Thousand Oaks, CA 91320 USA

[3] Amgen Inc, Dept Metab Disorders, Thousand Oaks, CA 91320 USA

[4] Amgen Inc, Dept Pharmacokinet & Drug Metab, Thousand Oaks, CA 91320 USA

[5] Amgen Inc, Dept Pathol, Thousand Oaks, CA 91320 USA

[6] Amgen Inc, Dept Pharmaceut, Thousand Oaks, CA 91320 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 02期

关键词：

DIABETES THERAPY; ACTIVATORS;

D O I：

10.1021/jm4016747

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

In the previous report, we described the discovery and optimization of novel small molecule disruptors of the GK-GKRP interaction culminating in the identification of 1 (AMG-1694). Although this analogue possessed excellent in vitro potency and was a useful tool compound in initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by a combination of metabolite 27 identification and structure-based design, we have successfully discovered a potent and metabolically stable GK-GKRP disruptor (27, AMG-3969). When administered to db/db mice, this compound demonstrated a robust pharmacodynamic response (GK translocation) as well as statistically significant dose-dependent reductions in fed blood glucose levels.

引用

页码：325 / 338

页数：14

共 23 条

[21] Ethionamide Boosters. 2. Combining Bioisosteric Replacement and Structure-Based Drug Design To Solve Pharmacokinetic Issues in a Series of Potent 1,2,4-Oxadiazole EthR Inhibitors
Flipo, Marion
Desroses, Matthieu
Lecat-Guillet, Nathalie
Villemagne, Baptiste
Blondiaux, Nicolas
Leroux, Florence
Piveteau, Catherine
Mathys, Vanessa
Flament, Marie-Pierre
Siepmann, Juergen
Villeret, Vincent
Wohlkonig, Alexandre
Wintjens, Rene
Soror, Sameh H.
Christophe, Thierry
Jeon, Hee Kyoung
Locht, Camille
Brodin, Priscille
Deprez, Benoit
Baulard, Alain R.
Willand, Nicolas
JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (01) : 68 - 83
[22] Structure-based design of highly potent, specific, orally active small-molecule inhibitors of the MDM2-p53 interaction as a new class of anticancer therapy
Wang, Shaomeng
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2009, 238
[23] Structure-Based Design and in Silico Screening of Virtual Combinatorial Library of Benzamides Inhibiting 2-trans Enoyl-Acyl Carrier Protein Reductase of Mycobacterium tuberculosis with Favorable Predicted Pharmacokinetic Profiles
Kouman, Koffi Charles
Keita, Melalie
N'Guessan, Raymond Kre
Owono, Luc Calvin Owono
Megnassan, Eugene
Frecer, Vladimir
Miertus, Stanislav
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2019, 20 (19)

← 1 2 3 →