Quinazolinone derivatives as orally available ghrelin receptor antagonists for the treatment of diabetes and obesity.
The peptide hormone ghrelin is the endogenous ligand for the type 1a growth hormone secretagogue receptor (GHS-R1a) and the only currently known circulating appetite stimulant. GHS-R1a antagonism has therefore been proposed as a potential approach for obesity treatment. More recently, ghrelin has been recognized to also play a role in controlling glucose-induced insulin secretion, which suggests another possible benefit for a GHS-R1a antagonist, namely, the role as an insulin secretagogue with potential value for diabetes treatment. In our laboratories, piperidine-substituted quinazolinone derivatives were identified as a new class of small-molecule GHS-R1a antagonists. Starting from an agonist with poor oral bioavailability, optimization led to potent, selective, and orally bioavailable antagonists. In vivo efficacy evaluation of selected compounds revealed suppression of food intake and body weight reduction as well as glucose-lowering effects mediated by glucose-dependent insulin secretion.
Rudolph
Joachim
J
Department of Chemistry Research, Bayer Pharmaceuticals Corporation, 400 Morgan Lane, West Haven, Connecticut 06516, USA. rudolph.joachim@gene.com
Esler
William P
WP
O'connor
Stephen
S
Coish
Philip D G
PD
Wickens
Philip L
PL
Brands
Michael
M
Bierer
Donald E
DE
Bloomquist
Brian T
BT
Bondar
Georgiy
G
Chen
Libing
L
Chuang
Chih-Yuan
CY
Claus
Thomas H
TH
Fathi
Zahra
Z
Fu
Wenlang
W
Khire
Uday R
UR
Kristie
James A
JA
Liu
Xiao-Gao
XG
Lowe
Derek B
DB
McClure
Andrea C
AC
Michels
Martin
M
Ortiz
Astrid A
AA
Ramsden
Philip D
PD
Schoenleber
Robert W
RW
Shelekhin
Tatiana E
TE
Vakalopoulos
Alexandros
A
Tang
Weifeng
W
Wang
Lei
L
Yi
Lin
L
Gardell
Stephen J
SJ
Livingston
James N
JN
Sweet
Laurel J
LJ
Bullock
William H
WH
D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D001786:Blood Glucose / Q000032:analysis; D002460:Cell Line; D003920:Diabetes Mellitus / Q000188:drug therapy*; D004435:Eating / Q000187:drug effects; D005951:Glucose Tolerance Test; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy*; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015431:Weight Loss / Q000187:drug effects
C524277:6-(4-fluorophenoxy)-3-((1-isopropylpiperidin-3-yl)methyl)-2-methylquinazolin-4(3H)-one; C524276:6-(4-fluorophenyl)-2-isopropyl-3-((1-isopropylpiperidin-3-yl)methyl)quinazolin-4(3H)-one; D001786:Blood Glucose; D052999:Quinazolinones; D054440:Receptors, Ghrelin