Synthetic Inhibitors of Cytochrome P-450 2A6: Inhibitory Activity, Difference Spectra, Mechanism of Inhibition, and Protein Cocrystallization was written by Yano, Jason K.;Denton, Travis T.;Cerny, Matthew A.;Zhang, Xiaodong;Johnson, Eric F.;Cashman, John R.. And the article was included in Journal of Medicinal Chemistry in 2006.Electric Literature of C8H7N3 This article mentions the following:
A series of 3-heteroaromatic analogs of nicotine were synthesized to delineate structural and mechanistic requirements for selectively inhibiting human cytochrome P 450 (CYP) 2A6. Thiophene, substituted thiophene, furan, substituted furan, acetylene, imidazole, substituted imidazole, thiazole, pyrazole, substituted pyrazole, and aliphatic and isoxazol moieties were used to replace the N-methylpyrrolidine ring of nicotine. A number of potent inhibitors were identified, and several exhibited high selectivity for CYP2A6 relative to CYP2E1, -3A4, -2B6, -2C9, -2C19, and -2D6. The majority of these inhibitors elicited type II difference spectra indicating the formation of a coordinate covalent bond to the heme iron. The majority of inhibitors were reversible inhibitors although several mechanism-based inactivators were identified. Most of the inhibitors were also relatively metabolically stable. X-ray crystal structures of CYP2A6 cocrystd. with three furan analogs bearing methanamino side chains indicated that the amine side chain coordinated to the heme iron. The pyridyl moiety was positioned to accept a hydrogen bond from Asn297, and all three inhibitors exhibited orthogonal aromatic-aromatic interactions with protein side chains. For comparison, the cocrystal structure of 4,4′-dipyridyl disulfide was also obtained and showed that the pyridine moiety could assume a different orientation than that observed for the 3-heteroaromatic pyridines examined For the 3-heteroromatic pyridines, N-Me and N,N-di-Me amino groups increased the apparent Ki and distorted helix I of the protein. Substitution of a Ph ring for the pyridyl ring also increased the apparent Ki, which is likely to reflect the loss of the hydrogen bonding interaction with Asn297. In contrast, inhibitory potency for other P450s was increased, and the selectivity of the Ph analogs for CYP2A6 was decreased relative to the pyridyl compounds The results suggest that inhibitors that compliment the active site features of CYP2A6 can exhibit significant selectivity for CYP2A6 relative to other human liver drug-metabolizing P450s. In the experiment, the researchers used many compounds, for example, 3-(1H-Pyrazol-3-yl)pyridine (cas: 45887-08-9Electric Literature of C8H7N3).
3-(1H-Pyrazol-3-yl)pyridine (cas: 45887-08-9) belongs to pyrazole derivatives. Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The pyrazole ring is resistant to oxidation and reduction but the groups, such as alkyl and formyl attached to the ring, are oxidized to respective acids. Only electrolytic oxidation, ozonolysis, and a strong base cause ring opening.Electric Literature of C8H7N3
Referemce:
Pyrazole – Wikipedia,
Pyrazoles – an overview | ScienceDirect Topics