Solid Phase Synthesis of 1,5-Diarylpyrazole-4-carboxamides: Discovery of Antagonists of the CB-1 Receptor.
Summary of "Solid Phase Synthesis of 1,5-Diarylpyrazole-4-carboxamides: Discovery of Antagonists of the CB-1 Receptor."
We have developed a solid phase synthesis route to 1,5-substituted pyrazole-4-carboxamides with three diversity points aimed at the discovery of new compounds as potential G-Protein coupled receptor (GPCR) ligands. The new chemistry involves acylation of a resin bound secondary amine with a β-ketoester via transamidation, conversion of the resulting β-ketoamide to the corresponding vinylogous amide, pyrazole formation upon reaction with a aryl hydrzine, and cleavage of the product from the resin. Using the reported methodology, we describe the syntheses of multiple arrays of pyrazoles that were used collectively to construct a library of more than 1000 analogues. Several members of this library displayed submicromolar antagonist activities at the cannabinoid subtype 1 (CB-1) receptor.
Affiliation
Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
Journal Details
This article was published in the following journal.
Name: ACS combinatorial science
ISSN: 2156-8944
Pages: 197-204
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22340081
- DOI: http://dx.doi.org/10.1021/co200147y
Medical and Biotech [MESH] Definitions
Chromatography, Gas
Fractionation of a vaporized sample as a consequence of partition between a mobile gaseous phase and a stationary phase held in a column. Two types are gas-solid chromatography, where the fixed phase is a solid, and gas-liquid, in which the stationary phase is a nonvolatile liquid supported on an inert solid matrix.
Gels
Colloids with a solid continuous phase and liquid as the dispersed phase; gels may be unstable when, due to temperature or other cause, the solid phase liquefies; the resulting colloid is called a sol.
Solid Phase Extraction
An extraction method that separates analytes using a solid phase and a liquid phase. It is used for preparative sample cleanup before analysis by CHROMATOGRAPHY and other analytical methods.
Suspensions
Colloids with liquid continuous phase and solid dispersed phase; the term is used loosely also for solid-in-gas (AEROSOLS) and other colloidal systems; water-insoluble drugs may be given as suspensions.
G2 Phase
The period of the CELL CYCLE following DNA synthesis (S PHASE) and preceding M PHASE (cell division phase). The CHROMOSOMES are tetraploid in this point.
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