Douglas G. Batt

5-lipoxygenase inhibitors and their anti-inflammatory activities

A wide variety of agents have been reported as 5-LO inhibitors. The majority of the series appear to be lipophilic reducing agents, including phenols, partially saturated aromatics, and compounds containing heteroatom-heteroatom bonds. Many of these are not selective 5-LO inhibitors, but often affect CO and other LOs as well. In vivo systemic activity for many of these has been, in general, disappointing, probably because of poor bioavailability caused by lipophilicity and metabolic instability (oxidation, and conjugation of phenolic compounds). However, topically a number of agents have shown promise for skin inflammation, with Syntexs lonapalene the most advanced of these. Most results published to date appear more disappointing in the allergy/asthma field. More excitingly, a few structural types are selective 5-LO inhibitors which have shown systemic activity in vivo and in the clinic. Abbotts zileuton (136) appears to be one of the leading compounds in this category, along with other hydroxamates such as BW-A4C (129) from Burroughs-Wellcome. Recent selective non-reducing agents such as Wyeth-Ayersts Wy-50,295 (143) and the similar ICI compounds such as ICI 216800 (145) also hold promise. The enantiospecific effects of (106) and (145) are especially interesting for the design of new inhibitors. If compounds like these validate the hypothesis that inhibition of 5-LO will have a significant anti-inflammatory effect, a redoubling of effort throughout the industry to find second- and third-generation selective agents may be expected. Part of the difficulty in interpreting and comparing the 5-LO literature is the plethora of test methods and activity criteria. As pointed out in the introduction, inhibition of product release from cells, often stimulated with A23187, has commonly been used to demonstrate 5-LO inhibition. However, this type of assay cannot be assumed to be diagnostic for 5-LO inhibition. Only if specificity for 5-LO product generation and (ideally) activity in cell-free enzymes is also shown should mechanistic interpretations be made. Recently, a new class of compounds was found at Merck which inhibited LT biosynthesis without inhibiting 5-LO, but apparently by a novel, specific mechanism. L-655,240 (169) and L-663,536 (MK-886) (170) were both active in human ISN, with IC50 values in the low micromolar range. Both also orally inhibited GPB (< 1 mg/kg). MK-886 was effective in Ascaris-induced asthma in squirrel monkeys, in rat carrageenan pleurisy, in rat Arthus pleurisy, and (topically) in guinea-pig ear oedema induced by A23187.(ABSTRACT TRUNCATED AT 400 WORDS)

Heteroatom- and carbon-linked biphenyl analogs of Brequinar as immunosuppressive agents

Structure-activity relationships were explored for some analogs of Brequinar having a linking atom between the 2-biphenyl substituent and the quinoline ring. Activities as inhibitors of dihydroorotate dehydrogenase and the mixed lymphocyte reaction were related to the overall shape and lipophilicity of the 2-substituent.

CHEMISTRY AND PHARMACOKINETICS OF DIARYLTHIOPHENES AND TERPHENYLS AS SELECTIVE COX-2 INHIBITORS

Abstract DuP697, 2-bromo-4-(4′-sulfonylmethyl)phenyl-5-(4′-fluoro)phenylthiophene, is a selective type 2 cyclooxygenase (COX-2) inhibitor. Its relatively weak COX-2 selectivity coupled with a poor human pharmacokinetic profile led us to seek improvements on the in vitro selectivity while at the same time, addressing some of its pharmacokinetic liabilities. In this paper we discuss some strategies at solving the PK issue within a class of COX-2 inhibitors. The result of these efforts led to the discovery of a new class of COX-2 inhibitors the terphenyls, which prove to be superior alternatives to the diarylthiophenes.

Immunosuppressive structure-activity relationships of Brequinar and related cinchoninic acid derivatives

Abstract The immunosuppressive structure-activity relationships of substituted cinchoninic acid derivatives related to Brequinar were explored. Activities as inhibitors of dihydroorotate dehydrogenase and the mixed lymphocyte reaction were related to benzo-ring substitution, replacement of the benzo-ring by heterocycles, and variation in the 2-biphenyl, 3-methyl, and 4-carboxy groups.

Structure-activity relationships (SAR) of some tetracyclic heterocycles related to the immunosuppressive agent brequinar sodium

The structure-activity relationships of some tetracyclic heterocycles related to Brequinar were explored. Activities as inhibitors of dihydroorotate dehydrogenase and the mixed lymphocyte reaction are related to ring system, heteroatom placement, and pendant ring substitution.

Terphenyl cyclooxygenase-2 (COX-2) inhibitors: optimization of the central ring and o-biphenyl analogs.

The discovery of terphenyl derivatives as highly selective COX-2 inhibitors resulted from our efforts to overcome poor pharmacokinetics demonstrated by the COX-2 selective diarylthiophene DuP 697 [2-bromo-4-(4-sulfonylmethyl)phenyl-5-(4-fluoro)phenylthiophe ne]. Detailed SAR related to the ortho-biphenyls and variants of the central ring are described herein.

Rapid synthesis of RGD mimetics with isoxazoline scaffolds on solid phase: Identification of αvβ3 antagonists lead compounds

Isoxazoline containing RGD mimetics were rapidly synthesized on a solid phase to optimize linkers, regioisomers of isoxazoline scaffolds, and exosite binding groups to yield lead αvβ3 antagonists.

Metabolism resistant isothiazolone inhibitors of cartilage breakdown

A series of 2-(arylmethyl)pyridoisothiazolones is reported that inhibit the IL-1 beta induced breakdown of bovine nasal septum cartilage in an organ culture assay. The synthesis and preliminary SAR of these compounds are described. These compounds represent a novel, non-peptide lead series approach to the mediation of the chronic cartilage breakdown associated with arthritic disease. These compounds are relatively resistant to reductive metabolism by liver microsomal preparations and appear to inhibit cartilage breakdown by interfering with the proteolytic activation of matrix metalloproteinases.

Topical anti-inflammatory activity of DuP 654, a 2-substituted 1-naphthol

Recent work suggests that one of the common biochemical characteristics of skin inflammatory diseases such as psoriasis is altered arachidonic acid metabolism with elevated levels of prostaglandins and leukotrienes. DuP 654, a 2-substituted 1-naphthol, is an exceptionally potent inhibitor of 5-lipoxygenase. DuP 654 was tested in various models of skin inflammation and was found to be potent at inhibiting edema induced by the topical application of arachidonic acid, tetradecanoyl phorbol acetate or the calcium ionophore A23187. DuP 654 was also effective in a murine model of contact sensitivity. DuP 654 was effective at reducing the numbers of infiltrating polymorphonuclear leukocytes in AA and TPA induced edema. These data, taken together, suggest that DuP 654 may be effective in treating human skin diseases.

Cellular and Biochemical Characterization of the Anti-Inflammatory Effects of DuP 654 in the Arachidonic Acid Murine Skin Inflammation Model (Part 1 of 2)

The possible utility of DuP 654, a potent 5-lipoxygenase inhibitor, for treating human inflammatory skin disease was investigated in murine skin treated with 1.0 mg arachidonic acid (AA). When DuP 654 was applied to murine skin treated with AA, it inhibited the resulting inflammation and influx of cells. High performance liquid chromatography and radioimmunoassay analysis of lipid extracts from AA-treated ears indicated that the influx of polymorphonuclear leukocytes (PMN) was temporally preceded by an appearance of significant amounts of 5-HETE (6.7 +/- 1.4 ng/ear) and Leukotriene B4 LTB4 0.92 +/- 0.2 ng/ear) when compared with extracts of untreated ears (5-HETE, 02 +/- 0.3 ng/ear; LTB4, less than 0.1 ng/ear). The levels of the 5-lipoxygenase products were reduced by treatment with 10 micrograms/ear DUP 654. Lipid extracts from AA-treated ears contain chemotactic activity for human PMN and this chemotactic activity in the AA-treated ears could be reduced but not eliminated by immunosorption with anti-LTB4 antibodies coupled to protein A-agarose. The appearance of the chemotactic activity was inhibited by DuP 654. Taken together, these data suggest that DuP 654 may have utility in human inflammatory skin disease.