Design, Synthesis, and Structure–Activity Relationships of Novel Pyrazolo[5,1-b]thiazole Derivatives as Potent and Orally Active Corticotropin-Releasing Factor 1 Receptor Antagonists

Abstract

This paper describes the design, synthesis, and structure-activity relationships of a novel series of 7-dialkylamino-3-phenyl-6-methoxy pyrazolo[5,1-b]thiazole derivatives for use as selective antagonists of the corticotropin-releasing factor 1 (CRF(1)) receptor. The most promising compound, N-butyl-3-[4-(ethoxymethyl)-2,6-dimethoxyphenyl]-6-methoxy-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[5,1-b][1,3]thiazole-7-amine (6t), showed high affinity (IC(50) = 70 nM) and functional antagonism (IC(50) = 7.1 nM) for the human CRF(1) receptor as well as dose-dependent inhibition of the CRF-induced increase in the plasma adrenocorticotropic hormone (ACTH) concentration at a dose of 30 mg/kg (po). Further, in the light/dark test in mice, the compound 6t showed anxiolytic activity at a dose of 30 mg/kg (po).

Scope of Selective Heterocycles from Organic and Pharmaceutical Perspective

“…In certain cases, reports on the less y Y. Takahashi et. al [168] described the synthesis and structure−activity relationships of a unique series of 7-dialkylamino-3-phenyl-6-methoxy pyrazolo [ for epilepsy and Alzheimer's disease [164], as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors [165], and as cAMP phosphodiesterase (PDE) III inhibitors for congestive heart catastrophe [166].…”

“…Sheme 76. sch76 Y. Takahashi et. al[168] described the synthesis and structure−activity relationships of a unique series of 7dialkylamino-3-phenyl-6-methoxy pyrazolo[5,1-b]thiazole derivatives to utilize as selective antagonists of the corticotropin-releasing factor 1 (CRF1) receptor. The best favorable compound, N-butyl-3-[4-(ethoxymethyl)-2,6dimethoxyphenyl]-6-methoxy-N-(tetrahydro-2H-pyran-4-yl)pyrazolo-[5,1-b, 1,3]thiazole-7-amine (169), exhibited very high affinity (IC50 = 70 nM) and functional antagonism (IC50 = 7.1 nM) for the human CRF1 receptor.…”

Synthesis, Characterization, and Biological Evaluation of Some Novel Pyrazolo[5,1-b]thiazole Derivatives as Potential Antimicrobial and Anticancer Agents

“…Figure 3 presents three examples of pharmacologically active pyrazolo[5,1- b ]thiazole derivatives: pyrazolo[5,1- b ]thiazole derivative (A) (a protein kinase inhibitor for treating cancer and other diseases) [ 31 ], pyrazolothiazole (B) (a potent corticotropin-releasing factor 1(CRF1) receptor antagonists) [ 32 ], and pyrazolo[5,1- b ]thiazole derivative (C) (possessing a strong suppressant function against the H37Ra strain) [ 33 ] ( Figure 3 ).…”

PPh3-Mediated [4 + 2]- and [4 + 1]-Annulations of Maleimides with Azoalkenes: Access to Fused Tetrahydropyridazine/Pyrrolidinedione and Spiro-dihydropyrazole/Pyrrolidinedione Derivatives

“…In the latter process with the stoichiometric amount of PPh 3 and acetone as solvent, the in situ formed phosphorus ylide was the key intermediate to realize the [4 + 1]-annulations. The obtained fused- and spiro-pyrrolidinedione derivatives are of great value in organic and medicinal chemistry, considering that the dihydropyrazole and tetrahydropyridazine moieties are widely existed in a plethora of pharmaceuticals and biologically active natural products. Both of the annulations share features such as exclusive regioselectivity, high yield, and broad substrate scope.…”