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The Mibefradil Derivative NNC55-0396, a Specific T-Type Calcium Channel Antagonist, Exhibits Less CYP3A4 Inhibition than Mibefradil

Molecular Toxicology Interdepartmental Program (P.H.B., O.H.), Department of Pathology and Laboratory Medicine (P.H.B., O.H.), Jonsson Comprehensive Cancer Center (P.H.B., O.H.), and Department of Neurobiology (A.Q.), University of California, Los Angeles, Los Angeles, California; and Neurology and Research Services, Veterans Affairs Greater Los Angeles, Los Angeles, California (A.Q., A.H.)

A novel mibefradil derivative, NNC55-0396, designed to be hydrolysis-resistant, was shown to be a selective T-type Ca²⁺ channel inhibitor without L-type Ca²⁺ channel efficacy. However, its effects on cytochromes P450 (P450s) have not previously been examined. We investigated the inhibitory effects of NNC55-0396 toward seven major recombinant human P450s—CYP3A4, CYP2D6, CYP1A2, CYP2C9, CYP2C8, CYPC19, and CYP2E1—and compared its effects with those of mibefradil and its hydrolyzed metabolite, Ro40-5966. Our results show that CYP3A4 and CYP2D6 are the two P450s most affected by mibefradil, Ro40-5966, and NNC55-0396. Mibefradil (IC₅₀ = 33 ± 3 nM, K_i = 23 ± 0.5 nM) and Ro40-5966 (IC₅₀ = 30 ± 7.8 nM, K_i = 21 ± 2.8 nM) have a 9- to 10-fold greater inhibitory activity toward recombinant CYP3A4 benzyloxy-4-trifluoromethylcoumarin-O-debenzylation activity than NNC55-0396 (IC₅₀ = 300 ± 30 nM, K_i = 210 ± 6 nM). More dramatically, mibefradil (IC₅₀ = 566 ± 71 nM, K_i = 202 ± 39 nM) shows 19-fold higher inhibition of CYP3A-associated testosterone 6β-hydroxylase activity in human liver microsomes compared with NNC55-0396 (IC₅₀ = 11 ± 1.1 µM, K_i = 3.9 ± 0.4 µM). Loss of testosterone 6β-hydroxylase activity by recombinant CYP3A4 was shown to be time- and concentration-dependent with both compounds. However, NNC55-0396 (K_I = 3.87 µM, K_inact = 0.061/min) is a much less potent mechanism-based inhibitor than mibefradil (K_I = 83 nM, K_inact = 0.048/min). In contrast, NNC55-0396 (IC₅₀ = 29 ± 1.2 nM, K_i = 2.8 ± 0.3 nM) and Ro40-5966 (IC₅₀ = 46 ± 11 nM, K_i = 4.5 ± 0.02 nM) have a 3- to 4-fold greater inhibitory activity toward recombinant CYP2D6 than mibefradil (IC₅₀ = 129 ± 21 nM, K_i = 12.7 ± 0.9 nM). Our results suggest that NNC55–0396 could be a more favorable T-type Ca²⁺ antagonist than its parent compound, mibefradil, which was withdrawn from the market because of strong inhibition of CYP3A4.