Design of pyrazolo-pyrimidines as 11β-HSD1 inhibitors through optimisation of molecular electrostatic potential

Abstract

The inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a potentially attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. A series of pyrazolo-pyrimidine inhibitors of this enzyme were identified from directed library synthesis. Knowledge of how these compounds bind to the enzyme and the key hydrogen-bonding interactions was used to design further compounds. The hydrogen-bond acceptor strength was calculated from the molecular electrostatic potential using quantum mechanical theory. Compounds were designed to modulate the acceptor strength, thus optimising the potency and other drug-like properties. Compounds with enhanced CNS penetration were designed through further modification of the electrostatic potential and the hydrogen-bond properties.