Design, synthesis, structural optimization, SAR, in silico prediction of physicochemical properties and pharmacological evaluation of novel & potent thiazolo [4,5-d]pyrimidine corticotropin releasing factor (CRF) receptor antagonists

Corticotropin-releasing factor (CRF) is a 41-amino-acid neuropeptide secreted from the hypothalamus and is the main regulator of the hypothalamus-pituitary-adrenocortical (HPA) axis. CRF is the master hormone which modulates physiological and behavioral responses to stress. Many disorders including anxiety, depression, addictive disorders and others are related to over activation of the CRF system. This suggests that new molecules which can interfere with CRF binding to its receptors may be potential candidates for neuropsychiatric drugs to treat stress-related disorders. Previously, three series of pyrimidine and fused pyrimidine CRF1 receptor antagonists were synthesized by our group and specific binding assays, competitive binding studies and determination of the ability to antagonize the agonist-stimulated accumulation of cAMP (the second messenger for CRF receptors) were reported. In continuation of our efforts in this direction, in the current manuscript, we report the synthesis & biological evaluation of a new series of CRF1 receptor antagonists. Seven compounds showed promising binding affinity with the best two compounds (compounds 6 & 43) displaying a superior binding affinity to all of our previous compounds. Compounds 6 & 43 have only 4 times and 2 times less binding affinity than the standard CRF antagonist antalarmin, respectively. Thus, our two best lead compounds (compound 6 & 43) can be considered potent CRF receptor antagonists with binding affinity of 41.0 & 19.2 nM versus 9.7 nM for antalarmin.

Automated summary

Corticotropin-releasing factor (CRF) is the main hormone involved in regulating the HPA axis and stress responses. Overactivation of the CRF system is associated with various disorders, including anxiety and depression. New molecules that can interfere with CRF receptor binding have potential as neuropsychiatric drugs for stress-related disorders. In this study, a new series of CRF1 receptor antagonists were synthesized and evaluated, with two compounds showing superior binding affinity compared to previous compounds. These lead compounds can be considered potent CRF receptor antagonists.