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Synthesis and evaluation of imidazole-dioxolane compounds as selective heme oxygenase inhibitors: effect of substituents at the 4-position of the dioxolane ring.

Abstract：

:Several imidazole-dioxolane compounds were synthesized and evaluated as novel inhibitors of heme oxygenase (HO). These compounds, which include a series of substituted thiophenol and substituted phenol derivatives of (2R,4S)-2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-4-[(phenylsulfanyl)methyl]-1,3-dioxolane hydrochloride (3), in addition to smaller functionalized derivatives, continue our structure-activity studies by exploration of the aminothiophenol region ('northeastern region') in our original target structure azalanstat (1). In vitro, most of the compounds in this series were found to be highly potent inhibitors of the stress-induced isozyme HO-1 and the constitutive isozyme HO-2, showing only moderate selectivity for HO-1. Nevertheless, a few of the compounds displayed higher selectivity toward HO-1. None of the compounds having a larger appendage in the northeastern region were inhibitors of CYP2E1, whereas a compound having a relatively small fluorine substituent in this region did inhibit CYP2E1; all of the compounds tested exhibited high inhibitory potency against CYP3A1/3A2.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Vlahakis JZ,Hum M,Rahman MN,Jia Z,Nakatsu K,Szarek WA

doi

10.1016/j.bmc.2009.01.078

subject

Has Abstract

pub_date

2009-03-15 00:00:00

pages

2461-75

issue

6

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(09)00129-1

journal_volume

17

pub_type

杂志文章

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