Optimization of 2,4-diaminopyrimidines as GHS-R antagonists: side chain exploration.
The synthesis and structure-activity relationships of the 4- and 6-substituents of 2,4-diaminopyrimidine-based growth hormone secretagogue receptor (GHS-R) antagonists are described. Diaminopyrimidines with 6-norbornenyl (4n) and 6-tetrahydrofuranyl (4p) substitutents were found to exhibit potent GHS-R antagonism and good selectivity (approximately 1000-fold) against dihydrofolate reductase.
Liu
Bo
B
Metabolic Disease Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6098, USA.
Liu
Mei
M
Xin
Zhili
Z
Zhao
Hongyu
H
Serby
Michael D
MD
Kosogof
Christi
C
Nelson
Lissa T J
LT
Szczepankiewicz
Bruce G
BG
Kaszubska
Wiweka
W
Schaefer
Verlyn G
VG
Falls
H Douglas
HD
Lin
Chun Wel
CW
Collins
Christine A
CA
Sham
Hing L
HL
Liu
Gang
G
D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D054440:Receptors, Ghrelin; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects
D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D013762:Tetrahydrofolate Dehydrogenase