2004

Fused pyrimidine derivativesR 0515 Optimization of 3-Phenylpyrazolo[1,5-a]pyrimidines as Potent Corticotropin-

Releasing Factor-1 Antagonists with Adequate Lipophilicity and Water Solubility. — To identify CRF1 antagonists possessing more hydrophilicity, several positions of the core structure of potent CRF1 antagonists are endowed with polar groups. The syn-theses of the title compounds start from phenylacetonitriles such as (I) and involve two subsequent cyclizations as the key steps. The syntheses are accomplished by alkylam-ination of chloropyrimidine derivative (VII). The 5-position bearing the optimal methyl group is very sensitive to any replacement while other positions tolerate small hydro-philic groups with slight reduction in binding affinity. Pyrazolopyrimidine (IXb) pos-sesses good binding affinity, potent functional antagonistic activity, and suitable lipo-philicity. Moreover, (IXb) possesses good plasma and brain exposure after oral admin-istration. — (CHEN*, C.; WILCOXEN, K. M.; HUANG, C. Q.; MCCARTHY, J. R.; CHEN, T.; GRIGORIADIS, D. E.; Bioorg. Med. Chem. Lett. 14 (2004) 14, 3669-3673; Dep. Med. Chem., Neurocrine Biosci., Inc., San Diego, CA 92121, USA; Eng.) — H. Hoennerscheid

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