T. P. Novozheeva

Amide- and urea-based synthetic anticonvulsants, antihypoxics, and inducers of the hepatic monooxygenase system. VII. Effect of benzhydrylureas on the cytochrome P-450-dependent liver monooxygenase system

54. D. M. Sedlock, R. A. Dobson, D. M. Deuel, et al., Antimicrob. Agents Chemother., 34, No. 4, 568-575 (1990). 55. S. Segeu, A. Barrilai, N. Rosen, and E. Rubinstein, Antimicrob. Agents Chemother., Abstract No. 385 (1988). 56. S. Segeu, A. Barrilai, N. Rosen, et al., Arch. Intern. Med., 149, No. 6, 1314-1316 (1989). 57. C. Siporin, et al. (eds.), The New Generation of Quinolones, New York-London (1990). 58. J. T. Smith and C. S. Levin, The Quinolones, V. T. Andriole (ed.), London (1988). 59. M. Soliati, D. Basetti, B. Datto!i, et al., Congress of Chemotherapy, Tokyo, pp. 1797!798 (1985). 60. R. Stahlman, Drugs Today, 24, 529-536 (1988). 61. R. W. Strunk, J. C. Gratz, R. Moserati, and W. M. Schell, Antimicrob. Agents Chemother., 28, 428-432 (1985). 62. P. van der Auwera, P. Grenier, Y. Glupczynki, and D. Picard, J. Antimicrob. Chemother., 2~, 209-219 (1989). 63. J. Vanderdouckt, A. Hellebrand, and R. Cordier, Curr. Ther. Res., 43, 82-91 (1988). 64. A. Vellucci, G. Bernardini, A. M. Battaglia, and P. Battaglia, Int. J. Clin. Pharmacol. Ther. Toxicol, 25, 279-281 (1987). 65. M. R. Wentland, The New Generation of Quinolones, C. Siporin, et al. (eds.), New York, Basel (1990), pp. 1-45. 66. W. J. A. Wijnands, A. J. A. Van Griethuysen, T. B. Vree, et al., J. Antimicrob. Chemother., i_88, 719-727 (1986). 67. W. J. A. Wijnands, T. B. Bree, A. M. Baars, et al., J. Antimicrob. Chemother., 21, 67-77 (1988). 68. L. S. Young, Ann. Intern. Med., 106, 144-146 (1987).

Amide- and urea-based synthetic anticonvulsants, antihypoxics, and inducers of the hepatic monooxygenase system. VIII. Effect of benzhydrylureas and m-chlorobenzhydrylureas on the rat liver monooxygenase system

Studies of the enzyme-inducing properties of a series of benzhydrylureas have established that the most active compounds are benzhydrylurea (I) and its m-chloro-substituted derivative (II), which produce pronounced reductions in the duration of hexobarbital sleep in mice, with parallel increases in the microsomal hemoprotein content [2]. Cytochrome P450 induction of the phenobarbital type was proposed to occur in mice receiving I and II. We report here our further studies on the effects of these compounds on the monooxygenase system of rat liver.

Enzyme-substrate complexes between diphenyl derivatives and microsomal cytochrome P-450. Electronic absorption spectra and dissociation constants

It was reported that some diphenyl derivatives may act as cytochrome P-450 inductors. These include polychlorinated diphenyls (possessing properties of inductors of the phenobarbital or methylcholanthrene type) [ 1 3 ] and aminodiphenyls [4]. Previously we have demonstrated that some substituted diphenyls, such as dibenzazepinone and diphenic acid anilides, also possess the properties of the phenobarbital-like inductors [5 7]. In this context, it was of interest to study the degree of affinity of these substances with respect to microsomal cytochrome P-450 because some published data are indicative of a relationship between the enzyme-inducing properties of the compounds and their ability to form complexes with microsomal hemoproteins [8, 9]. The purpose of this work was to investigate the differential electronic absorption spectra measured in the course of titration of a suspension of liver microsomes with solutions of compounds I VII. We have also determined the apparent dissociation constants K, of a series of enzymesubstrate complexes of the following types.

Inducers of the phenobarbital type (a review)

Over 30 years ago, Conney suggested the possibility of clinical application o f inducers of the monooxygenase system of the liver (MOSL) [1]. Among numerous compounds with enzyme-inducing properties, inducers of the phenobarbital type (PB inducers) are currently attracting major attention. They are used to correct the antitoxic function of the liver in its various pathologies, and as homeostatic modulators [2]. In addition to increasing the rate of metabolism of a large range ofsubstrates, the PB inducers considerably less often, in comparison with other inducers of the methylcholanthrene type (MC type), cause the toxification of xenobiotics and their acquisition of mutagenic, carcinogenic, and teratogenic properties. This is apparently associated with the fact that the substrates whose metabolism is accelerated with induction of the PB type do not include many xenobiotics whose toxicity substantially grows upon microsomal biotransformation in the liver, e.g., because of K-region formation [3]. The prospects for new PB-type inducers depend primarily on the degree of their specificity for various species. Thus, 1,4-bis(3,5-dichloro-2-pyridyloxy)benzene is effective for the MOSL of mice, but is inactive in rats; whereas 2,4,6-triphenyl1,3-dioxane induces the MOSL in rats, but not in mice [4]. Phenobarbital is a standard PB inducer having no specificity for various species. The present review presents the results of analyzing the structure activity relation for PB-type inducers with the aim of singling out the most general structural criteria encompassing all known inducers of this type.

Synthetic anticonvulsants, antihypoxics, and liver monooxygenase system inducers based on amides and urea. VI. Synthesis and search for liver monooxygenase system inducers among compounds containing the benzhydryl group

i. A. A. Bakibaev, L. G. Tignibidina, V. D. Filimonov, et al., Khim. Farm. Zh., No. 5, 31-35 (1991). 2. A. A. Bakibaev, V. D. Filimonov, V. K. Gorshkova, et al., Khim. Farm. Zh., No. 4, 34-36 (1993) . 3. E. V. M o n t s e v i c h y u t e g r i n g e n e , P a t . F i x i o l . , No. 4, 71-78 (1964) . 4. A. G. Pechenkin, L. G. Tingibidina, V. K. Gorshkova, et al., Khim. Farm. Zh., No. 5, 57-59 (1979). 5. V. D. Filimonov, A. A. Bakibaev, A. V. Pustovoitov, et al., Khim. Farm. Zh., No. 5, 540-545 (1988). 6. M. J. O r l o f f , H. L. Wi l l iams, and C. C. P f e i f e r , Proc. Soc. Exp. B io l . (N .Y . ) , 70, 254257 (1949). 7. E. A. Swinyard, W. C. Brown, and L. S. Goodman, J. Pharmacol. Exp. Ther., 106, 319-330 (1952).

Synthetic anticonvulsants, antehypoxants, and inducers of the hepatic monooxygenase system based on amides and ureas

A number of N-acyl derivatives of benzhydrylamine were previously synthesized and their anticonvulsant properties studied [2]. Several highly active compounds were found among these. It is known [3] that the trifluoroacetyl group frequently intensifies the biological effect of compounds. We therefore carried out the synthesis of N-(trifluoroacetyl)-N-(benzhydryl)amines I-X and established their anticonvulsant and antihypoxic properties and also their effect on the cytochrome P-450-dependent hepatic monooxygenase system. Trifluoroacetamides I-X were synthesized by reaction of benzhydrylamines (which in turn were obtained by the method we have described previously [2]) with trifluoroacetic anhydride in benzene at room temperature in good yield (75-86%).