Discovery of pyrrolo[2,3-d]pyrimidin-4-ones as corticotropin-releasing factor 1 receptor antagonists with a carbonyl-based hydrogen bonding acceptor

A new class of pyrrolo[2,3-d]pyrimidin-4-one corticotropin-releasing factor 1 (CRF1) receptor antagonists has been designed and synthesized. In general, reported CRF1 receptor antagonists possess a sp(2)-nitrogen atom as hydrogen bonding acceptor (HBA) on their core scaffolds. We proposed to use a carbonyl group of pyrrolo[2,3-d]pyrimidin-4-one derivatives as a replacement for the sp(2)-nitrogen atom as HBA in classical CRF1 receptor antagonists. As a result, several pyrrolo[2,3-d]pyrimidin-4-one derivatives showed CRF1 receptor binding affinity with IC50 values in the submicromolar range. Ex vivo I-125-sauvagine binding studies showed that 2-(dipropylamino)-3,7-dimethyl-5-(2,4,6-trimethylphenyl)-3,7-dihydro-4H-pyrrolo [2,3-d]pyrimidin-4-one (16b) (30 mg/kg, po) was able to penetrate into the brain and inhibit radioligand binding to CRF1 receptors (frontal cortex, olfactory bulb, and pituitary) in mice. We identified pyrrolo[2,3-d] pyrimidin-4-one derivatives as the first CRF1 antagonists with a carbonyl-based HBA. (C) 2011 Elsevier Ltd. All rights reserved.