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. 2024 Aug 1;29(15):3647.
doi: 10.3390/molecules29153647.

Design, Synthesis, and Biological Evaluations of Novel Thiazolo[4,5-d]pyrimidine Corticotropin Releasing Factor (CRF) Receptor Antagonists as Potential Treatments for Stress Related Disorders and Congenital Adrenal Hyperplasia (CAH)

Md Rabiul Islam  1 , Christos Markatos  2 , Ioannis Pirmettis  3 , Minas Papadopoulos  3 , Vlasios Karageorgos  2 , George Liapakis  2 , Hesham Fahmy  1
Affiliations

Design, Synthesis, and Biological Evaluations of Novel Thiazolo[4,5-d]pyrimidine Corticotropin Releasing Factor (CRF) Receptor Antagonists as Potential Treatments for Stress Related Disorders and Congenital Adrenal Hyperplasia (CAH)

Md Rabiul Islam et al. Molecules. .

Abstract

Corticotropin-releasing factor (CRF) is a key neuropeptide hormone that is secreted from the hypothalamus. It is the master hormone of the HPA axis, which orchestrates the physiological and behavioral responses to stress. Many disorders, including anxiety, depression, addiction relapse, and others, are related to over-activation of this system. Thus, new molecules that may interfere with CRF receptor binding may be of value to treat neuropsychiatric stress-related disorders. Also, CRF1R antagonists have recently emerged as potential treatment options for congenital adrenal hyperplasia. Previously, several series of CRF1 receptor antagonists were developed by our group. In continuation of our efforts in this direction, herein we report the synthesis and biological evaluation of a new series of CRF1R antagonists. Representative compounds were evaluated for their binding affinities compared to antalarmin. Four compounds (2, 5, 20, and 21) showed log IC50 values of -8.22, -7.95, -8.04, and -7.88, respectively, compared to -7.78 for antalarmin. This result indicates that these four compounds are superior to antalarmin by 2.5, 1.4, 1.7, and 1.25 times, respectively. It is worth mentioning that compound 2, in terms of IC50, is among the best CRF1R antagonists ever developed in the last 40 years. The in silico physicochemical properties of the lead compounds showed good drug-like properties. Thus, further research in this direction may lead to better and safer CRF receptor antagonists that may have clinical applications, particularly for stress-related disorders and the treatment of congenital adrenal hyperplasia.

Keywords: CRF receptor antagonists; antalarmin; congenital adrenal hyperplasia (CAH); thiazolo[4,5-d]pyrimidines.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Important CRF1R antagonists.
Figure 2
Figure 2
Structure of Tildacerfont and Crinecerfont.
Figure 3
Figure 3
General structure of synthesized analogs.
Figure 4
Figure 4
General synthetic scheme for intermediate and final target compounds.
Figure 5
Figure 5
% inhibition of [125I]-Try0 sauvagine-specific binding by 100 nM of test compounds on membranes from HEK293 stably expressing human CRF1 receptors. In the absence of the test compound, the inhibition is 0%.
Figure 6
Figure 6
Competitive binding isotherms of compounds 2, 5, and 14 (a), compounds 10 and 23 (b), compounds 19 and 20 (c) and 21 and 22 (d) to human CRF1 receptors. Antalarmin was used as a standard drug.
Figure 6
Figure 6
Competitive binding isotherms of compounds 2, 5, and 14 (a), compounds 10 and 23 (b), compounds 19 and 20 (c) and 21 and 22 (d) to human CRF1 receptors. Antalarmin was used as a standard drug.
Figure 7
Figure 7
Structure of compound 11 with more than four carbons at C-7 versus other two compounds (10 and 13) with 3–4 carbons in the side chain at C-7 position.
Figure 8
Figure 8
Representative compounds with different substituted phenyl groups at the N-3 position.
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