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Abstract: Based on a favorable balance between CRF-R1 affinity, lipophilicity and metabolic stability, compound 10 was evaluated for potential development as PET radioligand. Compound [18F]10 was prepared with high radiochemical purity and showed promising binding properties in rat brain imaging experiments. [Copyright &y& Elsevier]

Abstract: A series of pyrazinones were prepared and evaluated as potential CRF1R PET imaging agents. Optimization of their CRF1R binding potencies and octanol–phosphate buffer phase distribution coefficients are discussed herein. [Copyright &y& Elsevier]

The present studies have identified a series of diaminopyrimidines and diaminopyridines as novel 5-HT7 receptor ligands. Three regiosiomeric classes of pyrimidines and four regioisomeric classes of pyridines were synthesized and analyzed for binding to the 5-HT7 receptor. The 5-HT7 binding affinities of different regioisomers show clearly the structure–activity relationship with position of ring nitrogens. [Copyright &y& Elsevier]

Evidence suggests that corticotropin-releasing factor-1 (CRF(1)) receptor antagonists may offer therapeutic potential for the treatment of diseases associated with elevated levels of CRF such as anxiety and depression. A pyrazinone-based chemotype of CRF(1) receptor antagonists was discovered. Structure-activity relationship studies led to the identification of numerous potent analogues including 12p, a highly potent and selective CRF(1) receptor antagonist with an IC(50) value of 0.26 nM. The pharmacokinetic properties of 12p were assessed in rats and Cynomolgus monkeys. Compound 12p was efficacious in the defensive withdrawal test (an animal model of anxiety) in rats. The synthesis, structure-activity relationships and in vivo properties of compounds within the pyrazinone chemotype are described.

[reaction: see text] Substituted 1-tosyl-3-vinylindoles undergo catalytic asymmetric cyclopropanation with ethyl- and tert-butyldiazoacetate to afford N-protected trans-2-(indol-3-yl)-1-cyclopropanecarboxylic esters in good yield and high enantiomeric excess (81-88% ee). The resulting cycloadducts are demonstrated to be useful intermediates for the synthesis of conformationally restricted, homotryptamine-like analogues such as BMS-505130.