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Issue 5, 2015
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Design of pyrazolo-pyrimidines as 11β-HSD1 inhibitors through optimisation of molecular electrostatic potential

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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.

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

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Supplementary files

Article information


Submitted
30 Jan 2015
Accepted
26 Mar 2015
First published
30 Mar 2015

Med. Chem. Commun., 2015,6, 926-934
Article type
Concise Article
Author version available

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

G. R. Robb, S. Boyd, C. D. Davies, A. G. Dossetter, F. W. Goldberg, P. D. Kemmitt, J. S. Scott and J. G. Swales, Med. Chem. Commun., 2015, 6, 926
DOI: 10.1039/C5MD00043B

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