SAR studies of C2 ethers of 2H-pyrano[2,3-d]pyrimidine-2,4,7(1H,3H)-triones as nicotinic acid receptor (NAR) agonist.
Based on in house screening lead compound 1 for the NAR project, SAR studies have been focused on the modification of the C2 ethers of the pyrimidinedione core structure. In this effort, an unpredictable SAR trend was overcome in the alkyl ether and arylalkyl ether series to identify compound 24 with improved in vitro activity compared to nicotinic acid. More consistent and predictable SAR was achieved in the propargyl ether series. Lead compound 41 was identified with good in vitro and in vivo activity in rat, and much improved rat PK profile.
Department of Chemical Research, Merck Research Laboratory, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. xianhai.huang@merck.com
Xianhai
X
Huang
Jing
J
Su
Ashwin U
AU
Rao
Haiqun
H
Tang
Wei
W
Zhou
Xiaohong
X
Zhu
Xiao
X
Chen
Zhidan
Z
Liu
Ying
Y
Huang
Sylvia
S
Degrado
Dong
D
Xiao
Jun
J
Qin
Robert
R
Aslanian
Brian A
BA
McKittrick
Scott
S
Greenfeder
Margaret van
Mv
Heek
Madhu
M
Chintala
Anandan
A
Palani
D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
D004987:Ethers; D007783:Lactones; D011743:Pyrimidines; D011978:Receptors, Nicotinic