N-Nitropyrazoles, a New Class of NO-Generating Activators of Soluble Guanylate Cyclase

N. N. Belushkina,¹ N. B. Grigoryev,¹ and I. S. Severina^1,2

¹Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Pogodinskaya ul. 10, Moscow, 119832 Russia; fax: (095) 245-0857.

²To whom correspondence should be addressed.

Submitted June 26, 1997; revision submitted July 11, 1997.

---

A new class of activators of soluble guanylate cyclase, N-nitropyrazole derivatives, was investigated. Four N-nitropyrazole derivatives varying in their substitutes in positions 3 and 5 of the pyrazole ring were examined: 1-nitro- (1a), 1-nitro-3-methyl- (1b), 1-nitro-5-methyl- (1c), and 1-nitro-3,5-dimethyl- (1d) pyrazoles. By the readiness and intensity of NO-formation in the course of electrochemical and chemical reduction of the studied N-nitropyrazoles, they may be divided into 2 groups: the first group includes compounds 1a-1c with insignificant NO generation (1-3%); second group is represented by compound 1d which is characterized by considerable (up to 60%) NO formation. In full accordance with the intensity of NO formation from these compounds is their ability to activate guanylate cyclase. Compounds 1a-1c (0.01 mM) only insignificantly (up to 30-70%) increase the enzyme activity. Compound 1d activates guanylate cyclase up to 403 and 426% at concentration 0.01 and 0.1 mM, respectively. The correlation between spasmolytic activity of the studied N-nitropyrazoles and the ability of these compounds to activate guanylate cyclase suggests that their biological action is based on NO release as a result of their biotransformation and guanylate cyclase activation.

---

KEY WORDS: guanylate cyclase, nitric oxide, N-nitropyrazoles.

---