Pyrazoles and pyrazolines as neural and inducible nitric oxide synthase (nNOS and iNOS) potential inhibitors (III)

• Published in: European journal of medicinal chemistry 2008-11, Vol.43 (11), p.2579-2591
• Main Authors: Carrión, M. Dora, López Cara, Luisa C., Camacho, M. Encarnación, Tapias, Víctor, Escames, Germaine, Acuña-Castroviejo, Darío, Espinosa, Antonio, Gallo, Miguel A., Entrena, Antonio
• Format: Article
• Language: English
• Subjects: Alkylation; Analytical, structural and metabolic biochemistry; Animals; Benzoyl-pyrazole; Benzoyl-pyrazoline; Biological and medical sciences; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Inducible nitric oxide synthase; Inhibition; Male; Medical sciences; Miscellaneous; Models, Molecular; Molecular Structure; Neural nitric oxide synthase; Nitric Oxide Synthase Type I - antagonists & inhibitors; Nitric Oxide Synthase Type I - metabolism; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitric Oxide Synthase Type II - metabolism; Oxidoreductases; Pharmacology. Drug treatments; Protein Binding; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Rats; Rats, Wistar; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2008.01.014

We have previously described a series of 4,5-dihydro-1 H-pyrazole as moderately potent nNOS inhibitors. As a follow up of these studies, we report here the preparation and the preliminary evaluation of a series of 1-alkyl-3-benzoyl-4,5-dihydro-1 H-pyrazole and 1-alkyl-3-benzoyl-1 H-pyrazole as potential inhibitors of both neuronal and inducible nitric oxide synthases (nNOS and iNOS). None of the reported compounds exhibited significant iNOS or nNOS inhibition, although the 1-benzyl-3-(2-amino-5-chlorobenzoyl)-1 H-pyrazole-5-carboxylic acid ethyl ester derivative ( 10l), which shows an inhibition of 50% versus iNOS at a 1 mM final concentration and no activity against nNOS, is potentially amenable of further optimization. The reasons for the inactivity of the reported series are discussed on the basis of docking studies. [Display omitted] The synthesis and preliminary evaluation of a series of 1-alkyl-3-benzoyl-4,5-dihydro-1 H-pyrazole and 1-alkyl-3-benzoyl-1 H-pyrazole as potential inhibitors of both neuronal and inducible nitric oxide synthases (nNOS and iNOS) are described.