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.
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. phil.kym@abbott.com
Philip R
PR
Kym
Andrew J
AJ
Souers
Thomas J
TJ
Campbell
John K
JK
Lynch
Andrew S
AS
Judd
Rajesh
R
Iyengar
Anil
A
Vasudevan
Ju
J
Gao
Jennifer C
JC
Freeman
Dariusz
D
Wodka
Mathew
M
Mulhern
Gang
G
Zhao
Seble H
SH
Wagaw
James J
JJ
Napier
Sevan
S
Brodjian
Brian D
BD
Dayton
Regina M
RM
Reilly
Jason A
JA
Segreti
Ryan M
RM
Fryer
Lee C
LC
Preusser
Glenn A
GA
Reinhart
Lisa
L
Hernandez
Kennan C
KC
Marsh
Hing L
HL
Sham
Christine A
CA
Collins
James S
JS
Polakowski
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