Discovery of pyrrolo[2,3-d]pyrimidin-4-ones as corticotropin-releasing factor 1 receptor antagonists with a carbonyl-based hydrogen bonding acceptor
2011
Abstract A new class of pyrrolo[2,3- d ]pyrimidin-4-one corticotropin-releasing factor 1 (CRF 1 ) receptor antagonists has been designed and synthesized. In general, reported CRF 1 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 CRF 1 receptor antagonists. As a result, several pyrrolo[2,3- d ]pyrimidin-4-one derivatives showed CRF 1 receptor binding affinity with IC 50 values in the submicromolar range. Ex vivo 125 I-sauvagine binding studies showed that 2-(dipropylamino)-3,7-dimethyl-5-(2,4,6-trimethylphenyl)-3,7-dihydro-4 H -pyrrolo[2,3- d ]pyrimidin-4-one ( 16b ) (30 mg/kg, po) was able to penetrate into the brain and inhibit radioligand binding to CRF 1 receptors (frontal cortex, olfactory bulb, and pituitary) in mice. We identified pyrrolo[2,3- d ]pyrimidin-4-one derivatives as the first CRF 1 antagonists with a carbonyl-based HBA.
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