Selective thromboxane synthetase inhibitors. 1. 1-[(Aryloxy)alkyl]-1H-imidazoles

Abstract

1-(2-Phenoxyethyl)-1H-imidazole was found to be an inhibitor of thromboxane (TxA2) synthetase, but it also inhibited the adrenal cytochrome P-450 enzyme steroid 11 beta-hydroxylase. The preparation of a series of analogues is described, and activity against TxA2 synthetase, PGI2 synthetase, cyclooxygenase, and steroid 11 beta-hydroxylase is discussed. Potency against TxA2 synthetase was increased by introduction of a carboxyl group at a suitable distance from the imidazole ring. A distance of 8.1-8.8 A between N-1 of the imidazole and the carboxyl carbon was found to be optimal. Introduction of a carboxyl group also had the effect of reducing activity against steroid 11 beta-hydroxylase. The most potent and selective compound was found to be 4-[2-(1H-imidazol-1-yl) ethoxy]benzoic acid (14).

1-[(Aryloxy)alkyl]-1<I>H</I>-imidazoles as Inhibitors of Neuronal Nitric Oxide Synthase

“…Flash chromatography using Merck Silica gel 60 (0Á040±0Á063 mm) was used for preparative chromatographic separations. Imidazole and phenols 1a±k were purchased from Aldrich and (aryloxy)alkyl bromides 2a±m were prepared according to the procedure described by Cross et al (1985). Analytical and spectral data were in agreement with data in the literature.…”

“…The inhibitory effect of 1-substituted imidazoles 3a±m against nNOS, iNOS and eNOS was determined by monitoring the conversion of oxyhaemoglobin to methaemoglobin, according to Hevel & According to Cross et al (1985). b According to Robertson et al (1987) (percentage inhibition is expressed at 50 mM because of the very low solubility at higher concentrations).…”

“…General procedure for the synthesis of 1-[(aryloxy)alkyl]-1H-imidazoles 3a±m The procedure described by Cross et al (1985) was adopted with slight modi®cation. Sodium hydride 95% (7Á3 mmol) was added to a solution of imidazole (7Á3 mmol) in dry tetrahydrofuran and the mixture was stirred at room temperature for approximately 15 min.…”

“…To explore other molecules containing the imidazole nucleus as pharmacophore, we describe here the synthesis of a series of 1-[(aryloxy)alkyl]-1H-imidazoles, 3a±m, in which various phenoxy-ethyl, -propyl or -butyl chains were linked at the N-1 of the imidazole ring as potential selective inhibitors of nNOS. Some of these compounds have already been described in the literature as thromboxane synthetase inhibitors (3a, 3d, 3i;Cross et al 1985) or as anticonvulsants (3c; Robertson et al 1987).…”

High-throughput screening for inhibitors of Mycobacterium tuberculosis H37Rv

“…Nonetheless, many of them show sufficient selectivity to warrant further investigation. Such compounds have been previously reported to inhibit nitric oxide synthase34 and thromboxane synthetase,35 as well as to possess anticonvulsant36 and metamorphosis-inducing37 activities; we have not found any reports of antimicrobial activities of this class.…”