Structure and activity relationships leading to the discovery of ICI D2138, a selective, potent and orally active inhibitor of 5-lipoxygenase.

Structure and activity relationships of (methoxyalkyl)thiazole and 4-methoxytetrahydropyran series of 5-lipoxygenase inhibitors are reviewed. One member of the 4-methoxytetrahydropyran series, 6-([fluoro-5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy]methyl) -1- methylquinol-2-one (ICI D2138), is undergoing clinical evaluation.

Methoxyalkyl thiazoles: a novel series of potent, orally active and enantioselective inhibitors of 5-lipoxygenase.

Methoxyalkyl thiazoles are novel 5-lipoxygenase inhibitors which are neither redox agents nor iron chelators and are exemplified by ICI211965 [1-(3-(naphth-2-ylmethoxy)phenyl)-1-(thiazol-2-yl)prop yl methyl ether]. ICI211965 potently inhibits LTC4 synthesis in murine macrophages (IC50 = 0.0085 microM) and its selectivity with respect to cyclo-oxygenase (greater than 5800) is greater than any previously reported lipoxygenase inhibitor. ICI211965 also selectively inhibits LTB4 synthesis by human blood in vitro (IC50 = 0.45 microM) and rat blood ex vivo (ED50 = 10 mg/Kg, p.o.). Methoxyalkyl thiazoles exhibit a tight structure activity relationship and resolution of a chiral member of the series demonstrates that 5-lipoxygenase inhibition resides largely in one enantiomer. Methoxyalkyl thiazoles represent the first class of agents for which 5-lipoxygenase inhibition is mediated by specific, enantioselective interaction with the enzyme.

(Methoxyalkyl)thiazoles: a new series of potent, selective, and orally active 5-lipoxygenase inhibitors displaying high enantioselectivity.

(Methoxyalkyl)thiazoles are novel 5-lipoxygenase (5-LPO) inhibitors that are neither redox agents nor iron chelators. Consideration of a hypothetical model of the enzyme active site led to this series which is exemplified by 1-[3-(naphth-2-ylmethoxy)phenyl]-1-(thiazol-2-yl)propy l methyl ether (2d, ICI211965). 2d inhibits cell-free guinea pig 5-LPO activity, LTC4 synthesis in plasma free mouse macrophages, and LTB4 synthesis in rat and human blood (IC50s 0.1 microM, 8 nM, 0.5 microM, and 0.4 microM, respectively) but does not inhibit the synthesis of cyclooxygenase products at concentrations up to 50 microM in macrophages and 100 microM in blood. 2d is orally active in rat (ex vivo ED50 10 mg/kg in blood taken in 1 h after dosing). SAR studies show that high in vitro potency requires methoxy, thiazolyl, and naphthyl groups and depends critically on the substitution pattern. (Methoxyalkyl)thiazoles are chiral. Resolution of 1-methoxy-6-(naphth-2-ylmethoxy)-1-(thiazol-2-yl)indan (2j, ICI216800) shows that (+)-2j is 50-150-fold more potent than (-)-2j in in vitro assays. Thus, (methoxyalkyl)thiazoles are a new series of orally active, selective 5-LPO inhibitors and represent the first class of inhibitors in which inhibition is mediated by specific, enantioselective interactions with the enzyme.

Selective chiral inhibitors of 5-lipoxygenase with anti-inflammatory activity.

The studies described here, using enantiomers of an optically-active methoxy alkyl thiazole ICI216800 (1-methoxy-6-(naphth-2-yl-methoxyl)-1- (thiazol-2-yl)indane), provide unequivocal evidence for a specific, chiral interaction with 5-lipoxygenase. In accordance with their biochemical efficacy these compounds also demonstrate enantio-specific anti-inflammatory activity in a leukotriene-mediated model of inflammation. This is the first class of compounds for which 5-lipoxygenase inhibition and anti-inflammatory activity have been shown to be mediated via a specific chiral interaction.

The lysine pathway as a target for a new genera of synthetic antibacterial antibiotics?

Unsaturated analogues of diaminopimelic acid have been synthesized. The amino acids were designed so that they would be reversible or irreversible inhibitors of both of the two last enzymes of the lysine pathway. The compounds were tested with meso-diaminopimelate decarboxylase. trans-3,4-Didehydrodiaminopimelic acid (2) was found to be the most potent inhibitor. The antibacterial activities did not correlate with enzyme inhibiting activities. 4-Methylenediaminopimelic acid 4 showed strong antibacterial properties. It is suggested that L,L-diaminopimelate epimerase could be the target enzyme.

Synthesis of pseudotrisaccharides related to ribostamycin.

The three protected sisamine derivatives 2i, 2j and 3, with a free 5-hydroxyl group, have been synthesized. Glycosylation at the 5 position with various pentofuranose derivatives yielded after deprotection of the 6a approximately i ribostamycin related aminoglycoside. These pseudotrisaccharides showed only low antibacterial activities with respect to the parent compounds.

Synthesis of sisamine and of pseudodisaccharide analogues.

Lividamine and paromamine were converted into two key intermediate ethylenic aldehydes 10a and 10b. Reductive amination of the two aldehydes yielded the protected sisamine 11a and the three analogs 11b, 12a and 12b. These four derivatives were deprotected to yield the four pseudodisaccharides 1a, 1b, 2a and 2b which were less active in vitro than neamine against Escherichia coli ATCC 9637 and Staphylococcus aureus 209P.