title: 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.
abstract: 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.
authors.affiliation: 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
authors.forename: Richard A
authors.initials: RA
authors.lastname: Hartz
authors.forename: Kausik K
authors.initials: KK
authors.lastname: Nanda
authors.forename: Charles L
authors.initials: CL
authors.lastname: Ingalls
authors.forename: Vijay T
authors.initials: VT
authors.lastname: Ahuja
authors.forename: Thaddeus F
authors.initials: TF
authors.lastname: Molski
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.forename: Yong
authors.initials: Y
authors.lastname: Peng
authors.forename: Michelle
authors.initials: M
authors.lastname: Kelley
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lodge
authors.forename: Robert
authors.initials: R
authors.lastname: Zaczek
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Gilligan
authors.forename: George L
authors.initials: GL
authors.lastname: Trainor
mesh_terms: 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
chemical_list: D011687:Purines; D018019:Receptors, Corticotropin-Releasing Hormone; D000242:Cyclic AMP; C030985:purine