Highly selective inhibitors of thromboxane synthetase. 2. Pyridine derivatives

Abstract

The enzyme thromboxane (TX) synthetase is inhibited by pyridine. The beta-substituted pyridine derivatives showed higher inhibitory potency than the gamma-substituted ones having the same side chain. Among the beta-substituted derivatives containing the omega-carboxyalkyl group, the compounds with 6-8 carbon atoms in the side chain were especially effective. The derivatives holding the phenylene group in the side chain exhibited much higher inhibitory activity than those of the alkylene type. Among them, (E)-3-[4-(3-pyridylmethyl)phenyl]-2-methylacrylic acid hydrochloride (5a) had the highest potency (IC50 = 3 x 10(-9) M). The beta-substituted pyridine derivatives and 1-substituted imidazole derivatives which had the same side chain showed almost the same potency. The beta-substituted pyridine derivatives do not inhibit arachidonic acid cyclooxygenase or prostaglandin I2 synthetase, two other enzymes of the arachidonic cascade.

A Novel Series of Thromboxane A2 Synthetase Inhibitors with Free Radical Scavenging and Anti-peroxidative Activities.

“…and a carboxylic acid, attached to an aromatic ring such as benzene, benzofuran, benzothiophene, indole or indane. [9][10][11][12][13] First, we synthesized five compounds, in which imidazole and carboxylic acid moieties were introduced at different positions on the indoline ring and examined their activities (Table 1). Compound 2 with an imidazole moiety at the 3-position and a carboxyl moiety at the 1-position showed an approximately 1.5-fold weaker inhibitory effect on arachidonate-induced aggregation than ozagrel, a selective TXA 2 synthetase inhibitor.…”

“…The position of the imidazole and the carboxylic acid on the aromatic ring and the distance between these functional groups are important for the activity of TXA 2 synthetase inhibitors. [9][10][11][12][13] Among the indoline-based derivatives, the position of two functional groups and the distance between them in compound 2 may be more favorable for interaction with TXA 2 synthetase than those in the other four compounds (3)(4)(5)(6). Compound 4 showed potent free radical scavenging activity comparable to those of ascorbic acid and a-tocopherol.…”

“…1). [9][10][11][12][13] We designed a series of indoline derivatives with a carboxyl and an imidazole moiety to find a novel TXA 2 synthetase inhibitor with free radical scavenging activity.…”

Human thromboxane synthase: comparative modeling and docking evaluation with the competitive inhibitors Dazoxiben and Ozagrel

“…These derivatives inhibitory effect has been previously proposed as dependent on the interaction between the basic nitrogen atom of the 1-imidazolyl or 3-imidazolyl rings with the heme iron 28,29 . This interaction allows the ligand to be in a parallel conformation to the plane of heme group, mimicking the binding mode of PGH2.…”

“…According to some structure-activity relationship (SAR) studies, molecules containing imidazole rings show higher inhibitory activity 28,29 . These studies have also shown that 1H-imidazol-1-yl derivatives vary in size (8.5-9.0 nm) and inhibitors with a carboxyl group and a hydrophobic side chain attached to the ring 2,5,8,28,29 are able to anchor the ligand in the TXAS active site by interaction with Arg374.…”