Discovery and Structure-Guided Optimization of Diarylmethanesulfonamide Disrupters of Glucokinase-Glucokinase Regulatory Protein (GK-GKRP) Binding: Strategic Use of a N → S (nN → σ*S-X) Interaction for Conformational Constraint

被引：30

作者：

Pennington, Lewis D. ^{[1
]}

Bartberger, Michael D. ^{[2
]}

Croghan, Michael D. ^{[1
]}

Andrews, Kristin L. ^{[2
]}

Ashton, Kate S. ^{[1
]}

Bourbeau, Matthew P. ^{[1
]}

Chen, Jie ^{[3
]}

Chmait, Samer ^{[2
]}

Cupples, Rod ^{[4
]}

Fotsch, Christopher ^{[1
]}

Helmering, Joan ^{[4
]}

Hong, Fang-Tsao ^{[1
]}

Hungate, Randall W. ^{[1
]}

Jordan, Steven R. ^{[2
]}

Kong, Ke ^{[1
]}

Liu, Longbin ^{[1
]}

Michelsen, Klaus ^{[2
]}

Moyer, Carolyn ^{[5
]}

Nishimura, Nobuko ^{[1
]}

Norman, Mark H. ^{[1
]}

Reichelt, Andreas ^{[1
]}

Siegmund, Aaron C. ^{[1
]}

Sivits, Glenn ^{[4
]}

Tadesse, Seifu ^{[1
]}

Tegley, Christopher M. ^{[1
]}

Van, Gwyneth ^{[5
]}

Yang, Kevin C. ^{[1
]}

Yao, Guomin ^{[1
]}

Zhang, Jiandong ^{[2
]}

Lloyd, David J. ^{[4
]}

Hale, Clarence ^{[4
]}

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

机构：

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

[2] Amgen Inc, Med Struct & Characterizat, Thousand Oaks, CA 91320 USA

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

[4] Amgen Inc, Metab Disorders Res, Thousand Oaks, CA 91320 USA

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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 24期

关键词：

SMALL-MOLECULE DISRUPTORS; DIABETES THERAPY; DRUG; ACTIVATORS; DERIVATIVES; DESIGN;

D O I：

10.1021/acs.jmedchem.5b01367

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The HTS-based discovery and structure-guided optimization of a novel series of GKRP-selective GK-GKRP disrupters are revealed. Diarylmethanesulfonamide hit 6 (hGK-hGKRP IC50 = 1.2 mu M) was optimized to lead compound 32 (AMG-0696; hcK hGKRP IC50 = 0.0038 mu M). A stabilizing interaction between a nitrogen atom lone pair and an aromatic sulfur system (n(N) -> sigma*(S-X)) in 32 was exploited to conformationally constrain a biaryl linkage and allow contact with key residues in GKRP. Lead compound 32 was shown to induce GI( translocation from the nucleus to the cytoplasm in rats (IHC score = 0; 10 mg/kg po, 6 h) and blood glucose reduction in mice (POC = -45%; 100 mg/kg po, 3 h). X-ray analyses of 32 and several precursors bound to GKRP were also obtained. This novel disrupter of GK-GKRP binding enables further exploration of GKRP as a potential therapeutic target for type II diabetes and highlights the value of exploiting unconventional nonbonded interactions in drug design.

引用

页码：9663 / 9679

页数：17

共 1 条

[1] Small molecule inhibitors for glucokinase-glucokinase regulatory protein (GK-GKRP) binding: Optimization for in vivo target assessment of type II diabetes
Siegmund, Aaron C.
Bourbeau, Matthew
St Jean, David J.
Bartberger, Michael D.
Pennington, Lewis D.
Norman, Mark H.
Hungate, Randy
Lloyd, David J.
Hale, Clarence
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2014, 248

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