A series of pyridine chromanols were synthesized and evaluated as LTD4-antagonists (LTD4-A). The quinoline sidechain of this class of such agents, as exemplified by REV-5901, has until now been deemed as essential for potent activity. However, by manipulating substituents on a pyridine ring, quinoline-like potency can be achieved. The results indicate that this is a function of pKa.The pharmacological modulation of the peptidoleukotrienes has been the subject of intensive efforts over the past decade and some of our efforts in this regard have been described in the previous paper. 1 In that article, we describe our early leukotriene D4 antagonist (LTD4-A) research program based on the weak antagonist REV-5901 1. The primary objective of the research program was to develop a more potent LTD4-A and this was achieved with the discovery of CP-80,798 2 as a clinical candidate for the treatment of asthma. The racemate of 2 had a K i of 1.64 ~ & 0.28, n = 5) as an inhibitor of [3H]-LTD4 binding in guinea pig lung membranes 2, compared to REV-5901 which has a Ki of 8.0 pM ~ 2.4, n = 4).One of the striking features of this quinoline class of compounds was the apparent necessity for the 2-substituted quinoline functionality for potent LTD4 antagonist activity, 3 which was observed in these Pfizer compounds as well. For example, a compound such as 3, where the quinoline has been replaced by a 2-substituted pyridine, did not inhibit [3H]-LTD4 binding in the guinea pig lung membrane assay (Ki > 100 p.M, n = 3).However, the idea of a monocyclic heterocyclic bioisostere for the quinoline ring 4 was appealing to us because we were interested in downsizing the molecule to improve its pharmacokinetic and physicochemical properties, as well as reducing its aromaticity. In addition, the introduction of structural diversity at this center was attractive as a goal. Therefore, a small synthetic program was undertaken with the aim of developing monocyclic heterocyclic quinoline replacements which maintain LTD4 antagonist activity, We found that by placing various substituents on the pyridine ring, we were able to reintroduce the LTD4 antagonist activity of the lead structure, and in fact improve it approximately 10 fold. This paper describes our findings on the relationship of pKa and IogP of the pyridine ring with respect to LTD4 receptor binding.