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

[1] Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 4. Exploration of a Novel Binding Pocket
Hong, Fang-Tsao
Norman, Mark H.
Ashton, Kate S.
Bartberger, Michael D.
Chen, Jie
Chmait, Samer
Cupples, Rod
Fotsch, Christopher
Jordan, Steven R.
Lloyd, David J.
Sivits, Glenn
Tadesse, Seifu
Hale, Clarence
St Jean, David J., Jr.
JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (14) : 5949 - 5964
[2] Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 1. Discovery of a Novel Tool Compound for in Vivo Proof-of-Concept
Ashton, Kate S.
Andrews, Kristin L.
Bryan, Marion C.
Chen, Jie
Chen, Kui
Chen, Michelle
Chmait, Samer
Croghan, Michael
Cupples, Rod
Fotsch, Christopher
Helmering, Joan
Jordan, Steve R.
Kurzeja, Robert J. M.
Michelsen, Klaus
Pennington, Lewis D.
Poon, Steve F.
Sivits, Glenn
Van, Gwyneth
Vonderfecht, Steve L.
Wahl, Robert C.
Zhang, Jiandong
Lloyd, David J.
Hale, Clarence
St Jean, David J., Jr.
JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (02) : 309 - 324
[3] Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis
Tamayo, Nuria A.
Norman, Mark H.
Bartberger, Michael D.
Hong, Fang-Tsao
Bo, Yunxin
Liu, Longbin
Nishimura, Nobuko
Yang, Kevin C.
Tadesse, Seifu
Fotsch, Christopher
Chen, Jie
Chmait, Samer
Cupples, Rod
Hale, Clarence
Jordan, Steven R.
Lloyd, David J.
Sivits, Glenn
Van, Gwyneth
Jean, David J. St., Jr.
JOURNAL OF MEDICINAL CHEMISTRY, 2015, 58 (11) : 4462 - 4482
[4] Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 1. Discovery of a Novel Tool Compound for in Vivo Proof-of-Concept (vol 57, pg 309, 2014)
Ashton, Kate S.
Andrews, Kristin L.
Bryan, Marian C.
Chen, Jie
Chen, Kui
Chen, Michelle
Chmait, Samer
Croghan, Michael
Cupples, Rod
Fotsch, Christopher
Helmering, Joan
Jordan, Steve R.
Kurzeja, Robert J. M.
Michelsen, Klaus
Pennington, Lewis D.
Poon, Steve F.
Sivits, Glenn
Van, Gwyneth
Vonderfecht, Steve L.
Wahl, Robert C.
Zhang, Jiandong
Lloyd, David J.
Hale, Clarence
St. Jean, David J., Jr.
JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (06) : 2820 - 2820
[5] Small Molecule Disruptors of the Glucokinase Glucokinase Regulatory Protein Interaction: 3. Structure Activity Relationships within the Aryl Carbinol Region of the N-Arylsulfonamido-N'-arylpiperazine Series
Nishimura, Nobuko
Norman, Mark H.
Liu, Longbin
Yang, Kevin C.
Ashton, Kate S.
Bartberger, Michael D.
Chmait, Samer
Chen, Jie
Cupples, Rod
Fotsch, Christopher
Helmering, Joan
Jordan, Steven R.
Kunz, Roxanne K.
Pennington, Lewis D.
Poon, Steve F.
Siegmund, Aaron
Sivits, Glenn
Lloyd, David J.
Hale, Clarence
St Jean, David J., Jr.
JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (07) : 3094 - 3116
[6] 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):
[7] Improved structure-based drug design with one million small molecule crystal structures
Kuhn, Bernd
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2019, 258
[8] 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
[9] Structure-Based Macrocycle Design in Small-Molecule Drug Discovery and Simple Metrics To Identify Opportunities for Macrocyclization of Small-Molecule Ligands
Cummings, Maxwell D.
Sekharan, Sivakumar
JOURNAL OF MEDICINAL CHEMISTRY, 2019, 62 (15) : 6843 - 6853
[10] Identification of small-molecule inhibitors of the steroidogenic acute regulatory protein (STARD1) by structure-based design
Akula, Nagaraju
Midzak, Andrew
Lecanu, Laurent
Papadopoulos, Vassilios
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (12) : 4139 - 4143

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