The present study describes the identification via privileged structure-based approach of the benzhydrylpiperazine moiety as a potential scaffold to develop novel CB(1) receptor modulators. Efficient structural optimization of the initial four hit compounds led to a high quality lead series, represented by compound 6c. Compound 6c is a highly potent and selective CB(1) receptor inverse agonist that is able to reduce body weight in diet-induced obese Sprague-Dawley rats. The preparation of privileged structure-based library, the progression from hit to lead, the structure-activity relationships in the lead series and in vitro and in vivo activity of compound 6c are discussed.
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