title: Optimization of 3-phenylpyrazolo[1,5-a]pyrimidines as potent corticotropin-releasing factor-1 antagonists with adequate lipophilicity and water solubility.
abstract: In our efforts to identify potent CRF(1) antagonists with proper physicochemical properties, a series of 3-phenylpyrazolo[1,5-a]pyrimidines bearing polar groups, such as amino, hydroxyl, methoxy, sulfoxide, were designed and synthesized. Several positions of the core structure were identified, where a polar group was tolerated with slight reduction in receptor binding. NBI 30545 (18n) was found to have good binding affinity and potent antagonistic activity at the human CRF(1) receptor. Moreover, this compound had proper lipophilicity (log D = 2.78) and good solubility in water (>10mg/mL), and exhibited good plasma and brain exposure when given orally.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121, USA. cchen@neurocrine.com
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.forename: Keith M
authors.initials: KM
authors.lastname: Wilcoxen
authors.forename: Charles Q
authors.initials: CQ
authors.lastname: Huang
authors.forename: James R
authors.initials: JR
authors.lastname: McCarthy
authors.forename: Takung
authors.initials: T
authors.lastname: Chen
authors.forename: Dimitri E
authors.initials: DE
authors.lastname: Grigoriadis
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D015195:Drug Design; D010949:Plasma / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry; D000099052:CRF Receptor, Type 1
chemical_list: C495822:NBI 30545; D011720:Pyrazoles; D011743:Pyrimidines; D018019:Receptors, Corticotropin-Releasing Hormone; D014867:Water; D000099052:CRF Receptor, Type 1; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP