PMID- 31519374
OWN - NLM
STAT- MEDLINE
DCOM- 20201022
LR  - 20201022
IS  - 1464-3405 (Electronic)
IS  - 0960-894X (Linking)
VI  - 29
IP  - 20
DP  - 2019 Oct 15
TI  - Discovery of potent and orally bioavailable indazole-based glucagon receptor 
      antagonists for the treatment of type 2 diabetes.
PG  - 126668
LID - S0960-894X(19)30618-3 [pii]
LID - 10.1016/j.bmcl.2019.126668 [doi]
AB  - Type 2 diabetes mellitus (T2DM) is characterized by chronically elevated plasma 
      glucose levels. The inhibition of glucagon-induced hepatic glucose output via 
      antagonism of the glucagon receptor (GCGR) using a small-molecule antagonist is a 
      promising mechanism for improving glycemic control in the diabetic state. The 
      present work discloses the discovery of indazole-based beta-alanine derivatives as 
      potent GCGR antagonists through an efficient enantioselective synthesis and 
      structure-activity relationship (SAR) exploration and optimization. Compounds 
      within this class exhibited excellent pharmacokinetic properties in multiple 
      preclinical species. In an acute dog glucagon challenge test, compound 13K 
      significantly inhibited glucagon-mediated blood glucose increase when dosed 
      orally at 10 mg/kg.
CI  - Copyright (c) 2019 Elsevier Ltd. All rights reserved.
FAU - Xu, Guozhang
AU  - Xu G
AD  - Discovery Sciences, Janssen Research & Development, L.L.C., Welsh & McKean Roads, 
      Spring House, PA 19477, USA. Electronic address: gxu4@its.jnj.com.
FAU - Gaul, Michael D
AU  - Gaul MD
AD  - Discovery Sciences, Janssen Research & Development, L.L.C., Welsh & McKean Roads, 
      Spring House, PA 19477, USA.
FAU - Song, Fengbin
AU  - Song F
AD  - Discovery Sciences, Janssen Research & Development, L.L.C., Welsh & McKean Roads, 
      Spring House, PA 19477, USA.
FAU - Du, Fuyong
AU  - Du F
AD  - Cardiovascular & Metabolic Research, Janssen Research & Development, L.L.C., 
      Welsh & McKean Roads, Spring House, PA 19477, USA.
FAU - Liang, Yin
AU  - Liang Y
AD  - Cardiovascular & Metabolic Research, Janssen Research & Development, L.L.C., 
      Welsh & McKean Roads, Spring House, PA 19477, USA.
FAU - DesJarlais, Renee L
AU  - DesJarlais RL
AD  - Discovery Sciences, Janssen Research & Development, L.L.C., Welsh & McKean Roads, 
      Spring House, PA 19477, USA.
FAU - DiLoreto, Karen
AU  - DiLoreto K
AD  - Discovery Sciences, Janssen Research & Development, L.L.C., Welsh & McKean Roads, 
      Spring House, PA 19477, USA.
FAU - Shook, Brian
AU  - Shook B
AD  - Discovery Sciences, Janssen Research & Development, L.L.C., Welsh & McKean Roads, 
      Spring House, PA 19477, USA.
FAU - Rentzeperis, Dennis
AU  - Rentzeperis D
AD  - Cardiovascular & Metabolic Research, Janssen Research & Development, L.L.C., 
      Welsh & McKean Roads, Spring House, PA 19477, USA.
FAU - Santulli, Rosie
AU  - Santulli R
AD  - Cardiovascular & Metabolic Research, Janssen Research & Development, L.L.C., 
      Welsh & McKean Roads, Spring House, PA 19477, USA.
FAU - Eckardt, Annette
AU  - Eckardt A
AD  - Cardiovascular & Metabolic Research, Janssen Research & Development, L.L.C., 
      Welsh & McKean Roads, Spring House, PA 19477, USA.
FAU - Demarest, Keith
AU  - Demarest K
AD  - Cardiovascular & Metabolic Research, Janssen Research & Development, L.L.C., 
      Welsh & McKean Roads, Spring House, PA 19477, USA.
LA  - eng
PT  - Journal Article
DEP - 20190904
PL  - England
TA  - Bioorg Med Chem Lett
JT  - Bioorganic & medicinal chemistry letters
JID - 9107377
RN  - 0 (Blood Glucose)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Indazoles)
RN  - 0 (Receptors, Glucagon)
RN  - 11P2JDE17B (beta-Alanine)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Blood Glucose/drug effects
MH  - Carbohydrate Metabolism
MH  - Diabetes Mellitus, Type 2/*drug therapy
MH  - Dogs
MH  - Dose-Response Relationship, Drug
MH  - Drug Evaluation, Preclinical
MH  - Humans
MH  - Hypoglycemic Agents/*chemical synthesis/pharmacokinetics
MH  - Indazoles/*chemistry
MH  - Liver/metabolism
MH  - Mice
MH  - Models, Molecular
MH  - Molecular Structure
MH  - Protein Binding
MH  - Rats
MH  - Receptors, Glucagon/*antagonists & inhibitors
MH  - Structure-Activity Relationship
MH  - beta-Alanine/*chemical synthesis/pharmacokinetics
OTO - NOTNLM
OT  - Diabetes mellitus
OT  - Glucagon receptor antagonist
OT  - Indazole
OT  - Molecular modeling
EDAT- 2019/09/15 06:00
MHDA- 2020/10/23 06:00
CRDT- 2019/09/15 06:00
PHST- 2019/06/10 00:00 [received]
PHST- 2019/08/30 00:00 [revised]
PHST- 2019/09/03 00:00 [accepted]
PHST- 2019/09/15 06:00 [pubmed]
PHST- 2020/10/23 06:00 [medline]
PHST- 2019/09/15 06:00 [entrez]
AID - S0960-894X(19)30618-3 [pii]
AID - 10.1016/j.bmcl.2019.126668 [doi]
PST - ppublish
SO  - Bioorg Med Chem Lett. 2019 Oct 15;29(20):126668. doi: 10.1016/j.bmcl.2019.126668. 
      Epub 2019 Sep 4.