title: Synthesis of 1-methyl-3-phenylpyrazolo[4,3-b]pyridines via a methylation of 4-phthalimino-3-phenylpyrazoles and optimization toward highly potent corticotropin-releasing factor type-1 antagonists.
abstract: 1-Methyl-3-phenylpyrazolo[4,3-b]pyridines were synthesized via a cyclization reaction of 1-methyl-4-amino-3-phenylpyrazoles 8 with ethyl acetoacetate. Optimization of this series of compounds resulted in CRF(1) antagonists with subnanomolar binding affinity. Compounds bearing a polar group such as methoxy or hydroxy were also found to be very active.
authors.affiliation: Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121, USA.
authors.forename: Charles Q
authors.initials: CQ
authors.lastname: Huang
authors.forename: Keith
authors.initials: K
authors.lastname: Wilcoxen
authors.forename: James R
authors.initials: JR
authors.lastname: McCarthy
authors.forename: Mustaph
authors.initials: M
authors.lastname: Haddach
authors.forename: Dimitri
authors.initials: D
authors.lastname: Grigoriadis
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
mesh_terms: D006801:Humans; D010797:Phthalimides / Q000138:chemical synthesis* / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099052:CRF Receptor, Type 1
chemical_list: D010797:Phthalimides; D011720:Pyrazoles; D011725:Pyridines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1