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

Charles Q Huang; Keith Wilcoxen; James R McCarthy; Mustaph Haddach; Dimitri Grigoriadis; Chen Chen

doi:10.1016/s0960-894x(03)00622-x

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

Bioorg Med Chem Lett. 2003 Oct 6;13(19):3371-4. doi: 10.1016/s0960-894x(03)00622-x.

Authors

Charles Q Huang¹, Keith Wilcoxen, James R McCarthy, Mustaph Haddach, Dimitri Grigoriadis, Chen Chen

Affiliation

¹ Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121, USA.

PMID: 12951128
DOI: 10.1016/s0960-894x(03)00622-x

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.

MeSH terms

Humans
Phthalimides / chemical synthesis*
Phthalimides / pharmacology
Pyrazoles / chemical synthesis*
Pyrazoles / pharmacology
Pyridines / chemical synthesis*
Pyridines / pharmacology
Receptors, Corticotropin-Releasing Hormone / antagonists & inhibitors*
Receptors, Corticotropin-Releasing Hormone / metabolism
Structure-Activity Relationship

Substances

Phthalimides
Pyrazoles
Pyridines
Receptors, Corticotropin-Releasing Hormone
CRF receptor type 1