Discovery of (2S)-N-[(1R)-2-[4-cyclohexyl-4-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperidinyl]-1-[(4-fluorophenyl)methyl]-2-oxoethyl]-4-methyl-2-piperazinecarboxamide (MB243), a potent and selective melanocortin subtype-4 receptor agonist.
We report the discovery and optimization of substituted 2-piperazinecarboxamides as potent and selective agonists of the melanocortin subtype-4 receptor. Further in vivo development of lead agonist, MB243, is disclosed.
Palucki
Brenda L
BL
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, USA. brenda_palucki@merck.com
Park
Min K
MK
Nargund
Ravi P
RP
Ye
Zhixiong
Z
Sebhat
Iyassu K
IK
Pollard
Patrick G
PG
Kalyani
Rubana N
RN
Tang
Rui
R
Macneil
Tanya
T
Weinberg
David H
DH
Vongs
Aurawan
A
Rosenblum
Charles I
CI
Doss
George A
GA
Miller
Randall R
RR
Stearns
Ralph A
RA
Peng
Qianping
Q
Tamvakopoulos
Constantin
C
McGowan
Erin
E
Martin
William J
WJ
Metzger
Joseph M
JM
Shepherd
Cherrie A
CA
Strack
Alison M
AM
Macintyre
D Euan
DE
Van der Ploeg
Lex H T
LH
Patchett
Arthur A
AA
D000818:Animals; D004285:Dogs; D007172:Erectile Dysfunction / Q000188:drug therapy; D000882:Haplorhini; D008297:Male; D051379:Mice; D009765:Obesity / Q000188:drug therapy; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists*
C500023:(2S)-N-((1R)-2-(4-cyclohexyl-4-(((1,1-dimethylethyl)amino)carbonyl)-1-piperidinyl)-1-((4-fluorophenyl)methyl)-2-oxoethyl)-4-methyl-2-piperazinecarboxamide; D010879:Piperazines; D010880:Piperidines; D044105:Receptor, Melanocortin, Type 4