Corticotropin-releasing factor (CRF) is a neuropeptide hormone which is secreted from the paraventricular nucleus of the hypothalamus and regulates the body's overall response to stress. It is the main regulator of the hypothalamus–pituitary–adrenocortical (HPA) axis. Numerous disorders including anxiety, depression, addictive disorders, Irritable Bowel Syndrome (IBS), cardiovascular diseases, and several other disorders of the immune system, as well as the reproductive system, are related to over activation of the CRF system. CRF exerts its action by binding to CRF receptors, especially CRF1 receptors. The involvement of CRF and its receptors in the CNS suggests that the molecules which can interfere with CRF functions and CRF binding to its receptors may be potential candidates for neuropsychiatric drugs to treat stress-related disorders. Previously, a few series of pyrimidine and fused pyrimidine CRF1R antagonists were synthesized and biologically evaluated by our group. In continuation of our effort to develop CRF1 receptors antagonist with superior binding affinity, a series of new compounds was synthesized as CRF1 R antagonist and biologically evaluated by two different assays including a specific binding assay and a competitive binding study on HEK-293 cells express human CRF1 receptors. Among the compounds of the new series, five compounds showed promising binding affinity to CRF1 receptors where the best compound has Log ki ± SE values of -7.39 ± 0.09 compared to standard drug antalarmin Log ki ± SE values is -8.01 ± 0.24. It is worth mentioning that the best compound of this new series (compound 6) showed superior binding affinity to CRF1 receptors to all of our previously synthesized compounds. It has only four times less binding affinity than the standard CRF1 antagonist antalarmin, which is a great improvement since our previous compounds had 10 times less binding affinity than antalarmin.

Design, synthesis, and biological evaluation of novel thiazolo[4,5-d]pyrimidine corticotropin-releasing factor (CRF) receptor antagonists with an improved affinity to CRF receptors

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.