Discovery of bombesin receptor subtype-3(BRS-3)agonists incorporating an antedrug approach aimed at peripheral mechanism of anti-obesity action.

Abstract

Bombesin receptor subtype-3 (BRS-3), known as a promising target for anti-obesity, is expressed not only in the brain but also in the intestine. Merck's clinical candidate, which showed anti-obesity effects in rats and dogs also caused cardiovascular (CV) adverse effects, such as an increase of body temperature, heart rate and blood pressure in animals. Hence, lowering the exposure of the compound to the brain is expected to avoid CV effects. We designed a novel bicyclic diazepine from a structural similarity between our compounds and Merck's candidate, and reduced brain penetration by lowering lipophilicity. To identify potent compounds without any CV effects on the central nerve system, a labile carboxylic ester with an antedrug functionality was introduced. Consequently, an antedrug, 5c, showed significant in vivo efficacy and no clear CV effect in dog iv infusion. Our study has paved the way for development of anti-obesity drugs with a safer profile.