Title
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
Document Type
Article
Publication Date
2-1-2022
Abstract
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 CRF 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 CRF 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.
Publication Source (Journal or Book title)
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
First Page
106084
Recommended Citation
Islam, M. R., Teleb, M., Karageorgos, V., Sakellaris, S., Papadopoulos, M., Pirmettis, I., Fronczek, F. R., Liapakis, G., & Fahmy, H. (2022). 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. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences, 169, 106084. https://doi.org/10.1016/j.ejps.2021.106084