Screening for cardiovascular safety: a structure-activity approach for guiding lead selection of melanin concentrating hormone receptor 1 antagonists.
An inactin-anesthetized rat cardiovascular (CV) assay was employed in a screening mode to triage multiple classes of melanin-concentrating hormone receptor 1 (MCHr1) antagonists. Lead identification was based on a compound profile producing high drug concentration in both plasma (>40 microM) and brain (>20 microg/g) with <15% change in cardiovascular endpoints. As a result of these stringent requirements, lead optimization activities on multiple classes of MCHr1 antagonists were terminated. After providing evidence that the cardiovascular liabilities were not a function of MCHr1 antagonism, continued screening identified the chromone-substituted aminopiperidine amides as a class of MCHr1 antagonists that demonstrated a safe cardiovascular profile at high drug concentrations in both plasma and brain. The high incidence of adverse cardiovascular effects associated with an array of MCHr1 antagonists of significant chemical diversity, combined with the stringent safety requirements for antiobesity drugs, highlight the importance of incorporating cardiovascular safety assessment early in the lead selection process.
Kym
Philip R
PR
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. phil.kym@abbott.com
Souers
Andrew J
AJ
Campbell
Thomas J
TJ
Lynch
John K
JK
Judd
Andrew S
AS
Iyengar
Rajesh
R
Vasudevan
Anil
A
Gao
Ju
J
Freeman
Jennifer C
JC
Wodka
Dariusz
D
Mulhern
Mathew
M
Zhao
Gang
G
Wagaw
Seble H
SH
Napier
James J
JJ
Brodjian
Sevan
S
Dayton
Brian D
BD
Reilly
Regina M
RM
Segreti
Jason A
JA
Fryer
Ryan M
RM
Preusser
Lee C
LC
Reinhart
Glenn A
GA
Hernandez
Lisa
L
Marsh
Kennan C
KC
Sham
Hing L
HL
Collins
Christine A
CA
Polakowski
James S
JS
D000818:Animals; D019440:Anti-Obesity Agents / Q000009:adverse effects / Q000097:blood / Q000138:chemical synthesis*; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002319:Cardiovascular System / Q000187:drug effects*; D045744:Cell Line, Tumor; D002867:Chromones / Q000009:adverse effects / Q000097:blood / Q000138:chemical synthesis*; D004285:Dogs; D007191:Indazoles / Q000009:adverse effects / Q000097:blood / Q000138:chemical synthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects; D010880:Piperidines / Q000009:adverse effects / Q000097:blood / Q000138:chemical synthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D019440:Anti-Obesity Agents; D002867:Chromones; D007191:Indazoles; C103263:MCHR1 protein, human; D010880:Piperidines; D017481:Receptors, Somatostatin