Inhibition of monoamine oxidase B by substituted benzimidazole analogues

Abstract

Both monoamine oxidase A and B (MAO-A and B) play an important role in the metabolism of monoamine neurotransmitters in the central nervous system (CNS) and are therefore of considerable pharmacological interest for the development of new drug therapies. Inhibitors of MA0 are of therapeutic interest for both the treatment of psychiatric and neurological diseases. Selective inhibitors of MAO-B are in use and are under investigation for the treatment of the symptoms and underlying neurodegeneration of Parkinson's disease (PD). PD is one of the most common neurological diseases of the elderly and is an idiopathic. slowly progressive, degenerative CNS disorder. At present the treatment of PD is mainly based on dopamine replacement therapy. The current treatment strategies for PD are believed to lack selectivity and may lead to severe side effects. These therapeutic strategies ameliorate the symptoms of the disease but do not prevent further progression of the disease. For this reason there are currently several studies underway to develop drugs that can delay or even halt the progression of the disease. Besides providing relief of the symptoms of PD, inhibition of MAO-B is also reported to exert a neuroprotective effect. Therefore, MAO-B may be an attractive alternative target for the development of drugs for the treatment of PD. Currently, the only MAO-B inhibitors that are used clinically are irreversible inactivators of the enzyme. Because of safety considerations it may be desirable to develop potent inhibitors of MAO-B that are reversible. A recent report of a small series of benzimidazole inhibitors of MAO-B has prompted us to study additional benzimidazole analogues in an attempt to develop compounds with improved potency. The principal objective of this study was to examine the MAO-B inhibition properties of a series of synthetic benzimidazole analogues in an effort to explore the possibility of designing inhibitors that are reversible while retaining their selectivity towards MAO-B. The study included the synthesis and characterization of a series of (E)-2-styryl-1-methylbenzimidazole analogues containing different substituents in the four position of the styryl ring. Also included in this study is 1-methylbenzimidazole. This compound was included in the study to investigate the importance of styryl substitution for MAO-B inhibition activity. This research forms part of a collaborative effort to discover new inhibitors of MAO-B that are reversible while retaining their selectivity towards MAO-B. Following the preparation of the target compounds, they were evaluated as MAO-B inhibitors in vitro using a spectrophotometric assay. The inhibition potencies were expressed as the enzyme-inhibitor dissociation constants (Ki values). The Ki values for the competitive inhibition of MAO-B by the test compounds were estimated by measuring the extent by which various concentrations of the test inhibitors slowed the rate of the oxidation of I-methyl-4-(Imethylpyrrol- 2-yl)-l.2,3,6-tetrahydropyridine (MMTP) to the corresponding dihydropyridinium metabolite (MMDP'). Lineweaver-Burke plots with increasing concentrations of the test inhibitors were constructed and the Ki values were determined. A Hansch type structureactivity relationship study indicated that the enzyme inhibition activity correlated with both the Tafl steric parameter and the lipophylicity of the substituent attached to the four position of the styryl ring. (E)-2-styryl-1-methylbenzimidazole analogues containing styryl ring substituents with a large degree of steric hindrance were found to be the most potent inhibitors. All of the benzimidazole analogues synthesized were found to be moderately potent reversible inhibitors of MAO-B. The modes of inhibition were found to be competitive with enzymeinhibitor dissociation constants (Ki values) in the low micro-molar range. The most potent compound was found to be (E)-2-(4-trifluoromethylstyryl)-l-methylbenzimidazole with a K, value of 0.56 pM. In accordance with the SAR study the trifluoromethyl substituent also had the highest degree of steric hindrance. 1-Methylbenzimidazole was found to be the least potent inhibitor of MAO-B. This suggests that the styryl functional group plays an important role in the interaction between the inhibitors and the active site of the enzyme.