Rapid parallel synthesis applied to the optimization of a series of potentnonpeptide neuropeptide Y-1 receptor antagonists

This study describes the integrated application of parallel synthesis and c omputational chemistry to the design of potent nonpeptide antagonists for t he neuropeptide Y-1 (NPY1) receptor. A lead molecule was modeled in the act ive site of the NPY1 receptor, and a potentially fruitful region for analog construction was identified. Synthesis of suitable scaffolds followed by s olution phase generation of a small library of analogs produced a compound with 5-fold improvement in binding over the already potent lead. This new c ompound was shown to be an unanticipated side product of the parallel synth esis reaction. (C) 1999 Elsevier Science Ltd. All rights reserved.