PMID- 29035567
OWN - NLM
STAT- MEDLINE
DCOM- 20171122
LR  - 20190115
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 60
IP  - 21
DP  - 2017 Nov 9
TI  - Hit-to-Lead Optimization and Discovery of 
      5-((5-([1,1'-Biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic 
      Acid (MK-3903): A Novel Class of Benzimidazole-Based Activators of AMP-Activated 
      Protein Kinase.
PG  - 9040-9052
LID - 10.1021/acs.jmedchem.7b01344 [doi]
AB  - AMP-activated protein kinase (AMPK) plays an essential role as a cellular energy 
      sensor and master regulator of metabolism in eukaryotes. Dysregulated lipid and 
      carbohydrate metabolism resulting from insulin resistance leads to hyperglycemia, 
      the hallmark of type 2 diabetes mellitus (T2DM). While pharmacological activation 
      of AMPK is anticipated to improve these parameters, the discovery of selective, 
      direct activators has proven challenging. We now describe a hit-to-lead effort 
      resulting in the discovery of a potent and selective class of benzimidazole-based 
      direct AMPK activators, exemplified by 
      5-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic 
      acid, 42 (MK-3903). Compound 42 exhibited robust target engagement in mouse liver 
      following oral dosing, leading to improved lipid metabolism and insulin 
      sensitization in mice.
FAU - Lan, Ping
AU  - Lan P
AUID- ORCID: 0000-0001-8728-180X
FAU - Romero, F Anthony
AU  - Romero FA
AUID- ORCID: 0000-0001-7917-1459
FAU - Wodka, Dariusz
AU  - Wodka D
FAU - Kassick, Andrew J
AU  - Kassick AJ
FAU - Dang, Qun
AU  - Dang Q
AD  - Metabasis Therapeutics, Inc. , 11119 North Torrey Pines Road, La Jolla California 
      92037, United States.
FAU - Gibson, Tony
AU  - Gibson T
AD  - Metabasis Therapeutics, Inc. , 11119 North Torrey Pines Road, La Jolla California 
      92037, United States.
FAU - Cashion, Daniel
AU  - Cashion D
AD  - Metabasis Therapeutics, Inc. , 11119 North Torrey Pines Road, La Jolla California 
      92037, United States.
FAU - Zhou, Gaochao
AU  - Zhou G
FAU - Chen, Yuli
AU  - Chen Y
FAU - Zhang, Xiaoping
AU  - Zhang X
FAU - Zhang, Aihua
AU  - Zhang A
FAU - Li, Ying
AU  - Li Y
FAU - Trujillo, Maria E
AU  - Trujillo ME
FAU - Shao, Qing
AU  - Shao Q
FAU - Wu, Margaret
AU  - Wu M
FAU - Xu, Shiyao
AU  - Xu S
FAU - He, Huaibing
AU  - He H
FAU - MacKenna, Deidre
AU  - MacKenna D
AD  - Metabasis Therapeutics, Inc. , 11119 North Torrey Pines Road, La Jolla California 
      92037, United States.
FAU - Staunton, Jocelyn
AU  - Staunton J
AD  - Metabasis Therapeutics, Inc. , 11119 North Torrey Pines Road, La Jolla California 
      92037, United States.
FAU - Chapman, Kevin T
AU  - Chapman KT
FAU - Weber, Ann
AU  - Weber A
FAU - Sebhat, Iyassu K
AU  - Sebhat IK
FAU - Makara, Gergely M
AU  - Makara GM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20171025
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Benzimidazoles)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Administration, Oral
MH  - Animals
MH  - Benzimidazoles/administration & dosage/*pharmacology/therapeutic use
MH  - Diabetes Mellitus, Type 2/*drug therapy
MH  - Drug Discovery
MH  - Insulin Resistance
MH  - Lipid Metabolism/drug effects
MH  - Mice
EDAT- 2017/10/17 06:00
MHDA- 2017/11/29 06:00
CRDT- 2017/10/17 06:00
PHST- 2017/10/17 06:00 [pubmed]
PHST- 2017/11/29 06:00 [medline]
PHST- 2017/10/17 06:00 [entrez]
AID - 10.1021/acs.jmedchem.7b01344 [doi]
PST - ppublish
SO  - J Med Chem. 2017 Nov 9;60(21):9040-9052. doi: 10.1021/acs.jmedchem.7b01344. Epub 
      2017 Oct 25.