Carl K. Buckner

Preclinical Exploration of the Potential Antiinflammatory Properties of the Peptide Leukotriene Antagonist ICI 204,219 (Accola™)

The search for antagonists of the leukotrienes or inhibitors of their production by the enzyme 5-lipoxygenase began in earnest over a decade ago following the disclosure of the structures of the leukotrienes LTB.,, LTC4, LTD4, and LTE, by Samuelsson et aL’ During the past few years, several highly potent and selective receptor antagonists-e.g., AccolateTM? SKF 104,353,3s4 MK5715-and synthesis inhibitors-e.g., D21386 and MK886’-have been discovered, with several entering clinical trials. Clinical findings reported to date indicate that these various compounds are capable of blocking or modulating bronchoconstriction induced by antigen, cold air, exercise, etc.a’6 While seductive, indeed, these clinical paradigms are not necessarily accurate predictors of efficacy in the “at large” asthma population. Thus, it has been heartening that early results reported from phase IIb and 111 trials also appear to demonstrate the efficacy of modulators of the leukotrienes. At the present time, it appears that the validity of the hypothesis that peptide leukotrienes are involved in the pathophysiology of allergic disease, specifically, asthma, is going to be verified. As a consequence, it became of interest to explore in greater depth the biological mechanism(s) responsible for this clinical activity. heclinical evaluation of the potential antiinflammatory properties of the peptide leukotriene antagonist AccolateTM was undertaken as a first step toward this goal.

The 5-lipoxygenase inhibitors ZD2138 and ZM230487 are potent and selective inhibitors of several antigen-induced guinea-pig pulmonary responses☆

The non-redox 5-lipoxygenase inhibitor Zeneca ZD2138 (6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy- methyl]-1-methyl-2-quinolone) was evaluated for its ability to inhibit antigen-induced leukotriene release from guinea-pig lung in vitro and antigen-induced increases in pulmonary resistance in guinea pigs in vivo. ZD2138 inhibited antigen-induced release of leukotriene D4 and leukotriene B4 with IC50 values of 0.3 +/- 0.06 microM and 0.4 +/- 0.09 microM, respectively. At about ten times higher concentrations, ZD2138 had no effect on antigen-induced release of thromboxane B2, indicating selectivity for inhibition of 5-lipoxygenase vs. phospholipase A2, cyclooxygenase, or thromboxane synthetase. Similarly, ZD2138 did not inhibit histamine release, indicating that the compound did not have a generalized effect on the mediator release processes. Zeneca ZM230487-(6-[(3-fluoro-5-[4-methoxy- 3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxymethyl]-1-ethyl-2-quinolone), the N-ethyl analog of ZD2138, was approximately equipotent toward inhibition of antigen-induced leukotriene D4 release, with an IC50 of 0.2 +/- 0.08 microM. The so-called 5-lipoxygenase activating protein (FLAP) inhibitor, MK-886 (3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-tert-butylthioindol-2-yl]-2 ,2- dimethylpropanoic acid), and the iron ligand 5-lipoxygenase inhibitor zileuton (N-(1-benzo[b]thien-2-ylethyl)-N-hydroxy-urea) were also active, but less potent than ZD2138 with IC50 values for inhibition of antigen-induced leukotriene release in vitro of 9.3 +/- 3.2 microM and 14.8 +/- 1.8 microM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Tachykinin-induced dyspnea in conscious guinea pigs☆

Aerosol administration of neurokinin A (NKA) or substance P (SP) to conscious guinea pigs produced labored abdominal breathing (dyspnea). Time to onset of dyspnea was inversely related to tachykinin concentration. Aerosol administration of the neutral endopeptidase inhibitor thiorphan significantly potentiated tachykinin-induced dyspnea without affecting responses to leukotriene D4 (LTD4), carbachol, histamine, platelet activating factor or serotonin (5-HT), indicating selectivity for tachykinins rather than a nonspecific effect on agonist reactivity. The rank order of potency for producing dyspnea was LTD4 greater than or equal to NKA (with thiorphan) much greater than SP (with thiorphan) greater than 5-HT = carbachol greater than histamine greater than platelet-activating factor. Pretreatment with propranolol, phentolamine, methysergide, pyrilamine or the peptide leukotriene antagonist, ICI 198,165, did not alter dyspnea induced by NKA or SP. The dose-response curves for NKA and SP were shifted to small degrees (less than 3-fold) to the right by atropine and to the left by indomethacin. Also, pretreatment with capsaicin did not affect responses to NKA or SP, indicating that they do not cause dyspnea by activating capsaicin sensitive C-fibers. These results suggest primarily direct effects of NKA and SP. This model may be useful for in vivo evaluation of tachykinin antagonists.

4-Alkylpiperidines related to SR-48968: Potent antagonists of the neurokinin-2 (NK2) receptor

A series of 4-alkylpiperidine derivatives related to the potent neurokinin-2 (NK2) receptor antagonist SR-48968 (1) is described. Simple aliphatic derivatives were found to be poorly active, but appropriate placement of an alcohol functional group afforded compounds that were of similar activity to 1. Several representatives in this series, such as the 4-(1-hydroxy-1-ethylpropyl)piperidine (14), were found to exhibit oral activity in a model of labored abdominal breathing in guinea pigs. These results expand the latitude of substituents available in this region of this series of NK2 receptor antagonists.

Substituted 2,4-diaminoquinazolines and 2,4-diamino-8-alkylpurines as antagonists of the neurokinin-2 (NK2) receptor

Abstract Modification of the heterocyclic nucleus of a lead pyrrolopyrimidine (1) found to be active as an antagonist at the neurokinin-2 (NK2) receptor is described. Compounds based on the purine nucleus (3) were found to be particularly interesting, and were modified in the C(2), C(4) and C(8) substituents to afford compounds with high potency.