4-[2-[Methyl(2-phenethyl)amino]-2-oxoethyl]-8-(phenylmethoxy)-2-naphthalenecarboxylic acid: a high affinity, competitive, orally active leukotriene B4 receptor antagonist

Abstract

Leukotriene B4 is a potent activator for polymorphonuclear (PMN) 1eukocytes.l It causes increased chemotactic and chemokinetic migration, aggregation, degranulation, lysosomal enzymes release, and free radical release. Because of these biological activities, LTB4 may play an important role in inflammatory diseases in which elevated levels of LTB4 have been detected, such as inflammatory bowel disease, rheumatoid arthritis, and psoriasis. The effects Of LTB4 are mediated through high-and low-affinity receptors on the surface of leukocytes. Since many receptor antagonists of other potent mediators have already demonstrated therapeutic value in man, the search for LTB4 receptor antagonists represents a rational therapeutic approach to inflammatory diseases. In this communication, we report the discovery of a potent new LTB4 antagonist.Several LTB4 receptor antagonists with a variety of biological activities have been reported in the literature. For example, SC-41930 (11, a well-studied LTB4 antagonist with multiple biological activities, exhibits only moderate binding affinity (ICs0 = 300 nM) to human neutrophils.2 Upjohn reported a series of LTB4 structure-based antagonists with ICs0 values ranging from 80 to 400 nM, but most of the compounds appear to exhibit mixed agonist/ antagonist a~tivity.~ Recently, Eli Lilly has reported LY 223982 (2) as a potent LTB4 antagonist with an ICs0 of 12 nM against human PMN LTB4 receptor^.^ ONO-LB-457 (3), which has a similar but slightly modified structure, is (1) For a recent review and relevent references, see: Kingsbury, W.; Daines, R.; Gleason, J.

Structure−Activity Relationships Study of Two Series of Leukotriene B4 Antagonists: Novel Indolyl and Naphthyl Compounds Substituted with a 2-[Methyl(2-phenethyl)amino]-2-oxoethyl Side Chain

“…By Scatchard analysis, 2a exhibited K i s of 0.14 and 2 nM for guinea pig and human PMN LTB 4 receptors, respectively. 2 SAR study of 2a was carried out in a manner similar to that described for 4a, and in general the results paralleled those obtained for the indole series. Thus, compounds 2b and 2c again demonstrated the importance of the substitution pattern on the central ring.…”

“…1 We have reported the synthesis RG 14893 (2a), a potent competitive LTB 4 receptor antagonist with oral inhibitory activity of the chemotaxis of PNMs to the LTB 4 -induced wheals in guinea pigs. 2 In the preceding paper 3 we have also described the development and structure-activity relationship study of a class of LTB 4 antagonists based on the phenylacetamide 3. Our study established that three structural features, namely (a) the 2-[methyl(2phenethyl)amino]-2-oxoethyl side chain, (b) an acid function, and (c) an additional lipophilic group, are required for high binding affinity with LTB 4 receptors.…”

A Novel Series of [2-[Methyl(2-phenethyl)amino]-2-oxoethyl]benzene-Containing Leukotriene B4 Antagonists: Initial Structure−Activity Relationships

“…Previously, we reported that 1 inhibited the GP spleen membrane and intact human PMN binding resulting in IC 50 values of 0.4 nM (vs 0.5 nM ligand) and 4.7 nM (vs 0.5 nM ligand), respectively. 3 In addition, 1 also exhibited an IC 50 of 0.96 nM in a GP whole cell PMN binding assay and, in a functional assay, it inhibited 1 nM LTB 4 -induced GP PMN aggregation with an IC 50 of 0.8 nM. The strong correlation between the binding affinity and functional antagonistic activity demonstrated that this compound is both a receptor binder and functional antagonist.…”

“…2 Recently, we reported that RG 14893 is a potent LTB 4 receptor antagonist with oral activity. 3 The synthesis of this compound evolved from our initial observation that a simple phenylacetamide derivative 2 displayed moderate competitive antagonist activity with an IC 50 of 4.7 µM in a broken-cell human polymorphonuclear leukocyte (PMN) LTB 4 binding assay. This unexpected activity led us to speculate that 2 had unusual structural features which could contribute to the binding affinity to the LTB 4 receptor.…”

(E)-3-[[[[6-(2-Carboxyethenyl)-5-[[8-(4-methoxyphenyl)octyl]oxy]-2-pyridinyl]methyl]thio]methyl]benzoic Acid and Related Compounds: High Affinity Leukotriene B4 Receptor Antagonists

“…13 The chiral LTB4 receptor antagonist SC-53228 (6, K = 1.3 nM) has been reported by Searle,14 and Rhdne-Poulenc Rorer has reported that RG 14893 (7) has a K of 2 nM on human PMNs. 15 The LTB4 receptor antagonist effort was initiated with the objective to discover novel antiinflammatory agents. As previously reported, using LTB4 (1) as a structural template the program quickly produced compounds with high receptor affinity.…”