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The SAR of a series of 7-chromanylacetic acids has been investigated with the aim of identifying potent and selective LTB4 receptor antagonists. We found optimal activity in derivatives with c~,c~-disubstitution on the acetic acid and a C-4 hydroxy group and a C-3 lipophilic group on the chromane ring. CP-105696 (43), which contains a 4-phenylbenzyl C-3 substituent, was selected for development. ~ 1997 Elsevier Science lad. LTB4 is a potent chemoattractant for granulocytes (e.g., neutrophils and eosinophils) and stimulates functional responses such as secretion and cytokine synthesis in these cells as well as in mononuclear cells and lymphocytes. Its presence in relevant tissues has implicated it to be a likely mediator in a number of inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, and asthma. Receptor antagonists of LTB4 are thus expected to be useful therapeutics tbr these diseases. To date, compounds from several structural classes have been discovered to display LTB4 antagonismJ During the course of our investigations on leukotriene D4 antagonists, we observed that certain chromanol derivatives displayed modest LTB4 antagonism in addition to LTD4 antagonism. We also noted that of all the NSAIDs examined, only the propionic acid class showed any significant parallel between their ability to block (3H) LTB4 binding to high affinity receptors on guinea pig spleen membranes and their ability to inhibit LTB4-induced human neutrophil chemotaxis} These observations led us to prepare hybrid molecules with the aim of identifying potent and selective LTB4 antagonists. Accordingly, the propionic acid derivatives 1

A series of pyridine chromanols were synthesized and evaluated as LTD 4 -antagonists (LTD 4 -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 combination of key structural pharmacophores found in known leukotriene D4 (LTD4) receptor antagonists with those of potent platelet activating factor (PAF) receptor antagonist UK-74,505 has led to the synthesis of hybrid compounds CP-96,021 and CP-96,486. These compounds represent the first known balanced, combined and orally active LTD4/PAF receptor antagonists.

The development of two novel LTD 4 receptor antagonists as clinical candidates for the treatment of asthma is described. The first generation compound, CP-80,798, was found to be a balanced 5-lipoxygenase inhibitor (5-LOI)/LTD 4 antagonist (LTD 4 -A), while the second generation compound, CP-85,958, is a selective LTD 4 antagonist.

The development of novel LTB 4 antagonists from a class of quinolylmethyl LTD 4 antagonists is described. These α-methyl quinolylmethyl chromanols were found to have good vitro activity.