Design, Synthesis, Structure Optimization, Structure-Activity Relationship (SAR), and Biological Evaluation of Novel and Potent Thiazolo[4,5-d]Pyrimidine Corticotropin Releasing Factor (CRF) Receptor Antagonists
Dissertation - Open Access
Doctor of Philosophy (PhD)
Department / School
Corticotropin-releasing factor (CRF) is a 41amino acid neuropeptide. It is secreted from the paraventricular nucleus of 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, Irritable Bowel Syndrome (IBS), cardiovascular diseases and several other disorders are related to over activation of the CRF system. CRF works through binding to CRF1 receptors. The involvement of CRF and its receptors in the CNS suggests that new molecules which can interfere with CRF binding to its receptors as well as the CRF function 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 were biologically evaluated using different assays. In continuation of our efforts in this direction, the objectives of this thesis were to synthesize different new series of compounds as CRF1 receptor antagonists with superior binding affinity and stablish SAR for this class of compounds as CRF1 receptor antagonist. A total of 74 new final compounds were synthesized and some of the representative compounds were biologically evaluated by two different assays including a specific binding assay and a competitive binding study. Among the 1st group of compounds, five compounds showed promising binding affinity to CRF1 receptors and the best compound binds to CRF1 receptor with a log Ki value of -7.39 ± 0.09 compared the logKi value of -8.01 ± 0.24 forantalarmin. Based on SAR studies of the1st group of compounds, the 2nd group of compounds were synthesized and were biologically evaluated. The best four compounds 39, 42, 57, 58 of the 2nd group have log IC50 values of -8.22 ± 0.33, -7.95 ± 0.26, -8.04 ± 0.16, -7.88 ± 0.09, respectively, compared to log IC50 ± SE value of -7.78 ± 0.21 for the standard drug antalarmin. This result indicates that compounds 39, 42, 57, 58 have better inhibitory effect than the standard drug antalarmin by 2.5, 1.4, 1.7, and 1.25 times, respectively. It is worth mentioning that the representative best compound (compound 39) showed superior inhibitory effect to all of our previously synthesized compounds. This is a great improvement from our previously-reported compounds which were 10 times less potent than antalarmin. In-silico physicochemical properties of some representative compounds showed better drug-able properties than antalarmin in-terms of Lipinski’s rules. Thus, our best lead compounds can be considered a potent CRF receptor antagonists and further research in this direction may lead to better and safer CRF receptor antagonists that may have clinical applications.
Number of Pages
South Dakota State University
Islam, Md Rabiul, "Design, Synthesis, Structure Optimization, Structure-Activity Relationship (SAR), and Biological Evaluation of Novel and Potent Thiazolo[4,5-d]Pyrimidine Corticotropin Releasing Factor (CRF) Receptor Antagonists" (2022). Electronic Theses and Dissertations. 439.
Available for download on Friday, August 15, 2025