M. McAuliffe

Discovery of MK-0476, a potent and orally active leukotriene D4 receptor antagonist devoid of peroxisomal enxyme induction

Abstract Structure-activity studies leading to the discovery of 1 (MK-0476) are described. The initial compound of this series, 2, was a potent leukotriene D4 (LTD4) antagonist, but was also a peroxisomal enzyme inducer in the mouse. Structure-activity relationships around the thioether chain were explored to remove this undesirable feature. It was found that alkyl substituents in the s position relative to the carboxylic acid reduce the potency as a peroxisomal enzyme inducer while preserving the LTD4 antagonistic properties. Dialkyl substitution essentially eliminates the enzyme induction. The optimal styryl quinoline 1 exhibited high in vitro potency and in vivo activity on oral dosing without significant liver enzyme induction in the mouse.

Discovery of L-791,943: A potent, selective, non emetic and orally active phosphodiesterase-4 inhibitor

Structure-activity relationship studies directed toward improving the potency and metabolic stability of CDP-840 (3) resulted in the discovery of L-791,943 (11n) as a potent (HWB TNF-alpha = 0.67 microM) and orally active phosphodiesterase type 4 (PDE4) inhibitor. This compound, which bears a stable bis-difluoromethoxy catechol and a pendant hexafluorocarbinol, exhibited a long half-life in rat and in squirrel monkey. It is well tolerated in ferret with an emetic threshold greater than 30 mg/kg (po) and was found to be active in the ovalbumin-induced bronchoconstriction model in guinea pig and in the ascaris-induced bronchoconstriction models in sheep and squirrel monkey.

The discovery of a new structural class of potent orally active leukotriene D4 antagonists

Abstract A new, potent, orally active leukotriene D 4 receptor antagonist has been discovered. The structure -activity relationship leading to L-695,499 is described.

Substituted 4-(2,2-diphenylethyl)pyridine-N-oxides as phosphodiesterase-4 inhibitors: SAR study directed toward the improvement of pharmacokinetic parameters

A detailed SAR study directed toward the optimization of pharmacokinetic parameters for analogues of L-791,943 is reported. The introduction of a soft metabolic site on this structure permitted the identification of L-826,141 as a potent phosphodiesterase type 4 (PDE4) inhibitor that is well absorbed and that presents a shorter half-life than L-791,943 in a variety of animal species. The efficacy of L-826,141 is also demonstrated in different in vivo models.

Evolution of a series of non-quinoline leukotriene D4 receptor antagonist; synthesis and sar of benzothiazoles and thiazoles substituted benzyl alcohols as potent LTD4 antagonists

Abstract Replacement of the quinoline pharmacophore of verlukast by alkylthiazoles and benzothiazoles has lead to the discovery of a new series of potent and orally active LTD4 receptor antagonists. The synthesis and structure activity relationships of this series of compounds are described.

Substituted indoles as potent and orally active 5-lipoxygenase activating protein (FLAP) inhibitors

This paper reports on the SAR investigation of inhibitors of 5-lipoxygenase activating protein (FLAP) based on MK-0591. Emphasis was made on modifications to the nature of the link between the indole and the quinoline moieties, to the substitution pattern around the two heterocycles and to possible replacements of the quinoline moiety. Lead optimization culminated in (3-[1-(4-chlorobenzyl)-3-(t-butylthio)-5-(pyridin-2-ylmethoxy)-ind ol-2-yl]-2,2-dimethylpropanoic acid (18k), as a potent inhibitor of leukotriene biosynthesis that is well absorbed and active in functional models.

A series of non-quinoline cysLT1 receptor antagonists: SAR study on pyridyl analogs of Singulair

The structure-activity relationship of a series of styrylpyridine analogs of MK-0476 (montelukast, Singulair) is described. This work has led to the identification of a number of potent and orally active cysLT1 receptor (LTD4 receptor) antagonists including 2ab (L-733,321) as an optimized candidate.

The discovery of L-699,392, a novel potent and orally active leukotriene D4 receptor antagonist

The styryl quinoline thioether 5 (L-699,392) is a potent and orally active leukotriene D4 antagonist. The structure-activity studies leading to its discovery are described.

Discovery of L-740,515, a potent thienopyridine cysLT1 receptor (LTD4 receptor) antagonist

Abstract Structure-activity studies leading to the discovery of a new series of non-quinoline cysLT 1 receptor (LTD 4 receptor) antagonists are described. These studies demonstrated that the quinoline ring system of montelukast ( 5 ) may be replaced by an appropriately substituted thienopyridine system, yielding potent compounds. Two other molecular features of montelukast, the terminal phenyl ring substitution and the vinyl link, were also reevaluated. These studies led to the identification of 1 (L-740,515) , a compound with optimized in vitro and in vivo biological profiles.