Discovery and activity of (1R,4S,6R)-N-[(1R)-2-[4-cyclohexyl-4-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperidinyl]-1-[(4-fluorophenyl)methyl]-2-oxoethyl]-2-methyl-2-azabicyclo[2.2.2]octane-6-carboxamide (3, RY764), a potent and selective melanocortin subtype-4 receptor agonist.
A novel isoquinuclidine containing selective melanocortin subtype-4 receptor small molecule agonist, 3 (RY764), is reported. Its in vivo characterization revealed mechanism-based food intake reduction and erectile activity augmentation in rodents.
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, USA. zhixiong_ye@merck.com
Zhixiong
Z
Ye
Liangqin
L
Guo
Khaled J
KJ
Barakat
Patrick G
PG
Pollard
Brenda L
BL
Palucki
Iyassu K
IK
Sebhat
Raman K
RK
Bakshi
Rui
R
Tang
Rubana N
RN
Kalyani
Aurawan
A
Vongs
Airu S
AS
Chen
Howard Y
HY
Chen
Charles I
CI
Rosenblum
Tanya
T
MacNeil
David H
DH
Weinberg
Qianping
Q
Peng
Constantin
C
Tamvakopoulos
Randy R
RR
Miller
Ralph A
RA
Stearns
Doreen E
DE
Cashen
William J
WJ
Martin
Joseph M
JM
Metzger
Alison M
AM
Strack
D Euan
DE
MacIntyre
Lex H T
LH
Van der Ploeg
Arthur A
AA
Patchett
Matthew J
MJ
Wyvratt
Ravi P
RP
Nargund
D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects*; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010410:Penile Erection / Q000187:drug effects*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D011812:Quinuclidines / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists*; D012377:Rodentia; D013329:Structure-Activity Relationship; D013997:Time Factors
C504378:(1R,4S,6R)-N-((1R)-2-(4-cyclohexyl-4-(((1,1-dimethylethyl)amino)carbonyl)-1-piperidinyl-1-((4-fluorophenyl)methyl)-2-oxoethyl)-2-methyl-2-azabicyclo(2.2.2)octane-6-carboxamide); D001372:Aza Compounds; D010879:Piperazines; D010880:Piperidines; D011812:Quinuclidines; D044105:Receptor, Melanocortin, Type 4