Synthesis, in vitro biological investigation, and molecular dynamics simulations of thiazolopyrimidine based compounds as corticotrophin releasing factor receptor-1 antagonists

[Display omitted] •A series of new thiazolo[4,5-d]pyrimidine based CRFR1 antagonists was developed.•Compounds were screened through Inhibition of [125I]-Tyr0-sauvagine specific CRFR1 binding assay.•Compound 8c was the best candidate with Ki value of 32.1 nM.•Compound 8c Inhibited intracellular sauvagine-stimulated cAMP accumulation.•Molecular dynamics simulations studies showed allosteric inhibition mode similar to lead compound cp-376395. Corticotrophin releasing factor receptor-1 (CRFR1) is a potential target for treatment of depression and anxiety through modifying stress response. A series of new thiazolo[4,5-d]pyrimidine derivatives were designed, prepared and biologically evaluated as potential CRFR1 antagonists. Four compounds produced more than fifty percent inhibition in the [125I]-Tyr0-sauvagine specific binding assay. Assessment of binding affinities revealed that compound (3-(2,4-dimethoxyphenyl)-7-(dipropylamino)-5-methylthiazolo[4,5-d]pyrimidin-2(3H)-one) 8c was the best candidate with highest binding affinity (Ki = 32.1 nM). Further evaluation showed the ability of compound 8c to inhibit CRF induced cAMP accumulation in a dose response manner. Docking and molecular dynamics simulations were used to investigate potential binding modes of synthesized compounds as well as the stability of 8c-CRFR1 complex. These studies suggest similar allosteric binding of 8c compared to that of the co-crystalized ligand CP-376395 in 4K5Y pdb file.