Design, synthesis, and biological evaluation of 1,2,3,7-tetrahydro-6h-purin-6-one and 3,7-dihydro-1h-purine-2,6-dione derivatives as corticotropin-releasing factor(1) receptor antagonists.
A growing body of evidence suggests that CRF(1) receptor antagonism offers considerable therapeutic potential in the treatment of diseases resulting from elevated levels of CRF, such as anxiety and depression. A series of novel 1,2,3,7-tetrahydro-6H-purin-6-one and 3,7-dihydro-1H-purine-2,6-dione derivatives was synthesized and evaluated as corticotropin releasing factor-1 (CRF(1)) receptor antagonists. Compounds within this series, represented by compound 12d (IC(50) = 5.4 nM), were found to be highly potent CRF(1) receptor antagonists. In addition, compounds 12d and 12j were determined to be selective CRF(1) antagonists. The synthesis, structure-activity relationships and pharmacokinetic properties of compounds within this series is presented.
Hartz
Richard A
RA
Discovery Chemistry, Neuroscience Biology, and Metabolism and Pharmacokinetics, Bristol-Myers Squibb Company, Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut 06492, USA. richard.hartz@bms.com
Nanda
Kausik K
KK
Ingalls
Charles L
CL
Ahuja
Vijay T
VT
Molski
Thaddeus F
TF
Zhang
Ge
G
Wong
Harvey
H
Peng
Yong
Y
Kelley
Michelle
M
Lodge
Nicholas J
NJ
Zaczek
Robert
R
Gilligan
Paul J
PJ
Trainor
George L
GL
D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D006900:Hydroxylation; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D011687:Purines; D018019:Receptors, Corticotropin-Releasing Hormone; D000242:Cyclic AMP; C030985:purine