Synthesis and pharmacological characterization of a series of leukotriene analogs with antagonist and agonist activities

Abstract

The synthesis and biological characterization of a series of novel leukotriene antagonists and agonists are reported. All of these compounds are derivatives of (5S,6R,7Z)-5-hydroxy-6-mercapto-9-phenyl-7-nonenoic acid. One of the more potent compounds is (5S,6R,7Z)-6-[[(4-carboxy-2-methoxyphenyl)methyl]thio]-5-hydroxy-9 -(4- heptylphenyl)-7-nonenoic acid (3f). In vitro evaluation of this compound on guinea pig trachea revealed that it is a competitive antagonist of LTD4 and LTE4 with pKB values of 6.4 and 5.8, respectively. On guinea pig ileum, the pKB values obtained for it with LTD4 and E4 were both 7.2. The selectivity of 3f was shown by its lack of effect on carbachol, histamine, and barium chloride concentration-response curves in guinea pig trachea.

Opportunities and Challenges for Fatty Acid Mimetics in Drug Discovery

“…Another ligand-based method with LTD 4 as template led to success after addressing two problems: the unstable triene moiety had to be replaced by a more stable residue conserving potency, and the CysLT agonistic activity had to be turned to antagonism. On the basis of the nuclear magnetic resonance (NMR) data, leukotriene analogues ( 29 , Scheme ) mimicking the olefinic backbone by a homocinnamyl group were explored. , By variations in the peptide chain, they were turned into antagonists, but only ligands less potent than 24 were obtained . Then, the Merck group started similar investigations yet with decisive changes.…”

“…223,231 By variations in the peptide chain, they were turned into antagonists, but only ligands less potent than 24 were obtained. 232 Then, the Merck group started similar investigations yet with decisive changes. Using an entirely aromatic quinoline derivative (30) instead of homocinnamyl analogue as lead structure and mimetic for the olefinic backbone of LTD 4 , 233 they postulated that attachment of a carboxylic acid or peptide mimetic would further enhance potency (IC 50 = 6 μM).…”

Z‐Selective Hydrothiolation of Racemic 1,3‐Disubstituted Allenes: An Atom‐Economic Rhodium‐Catalyzed Dynamic Kinetic Resolution

“…[8] Since many bioactive compounds such as Montelukast, [9a] Hepatitis Cvirus NS3/4A inhibitors, [9b] and others [9c-e] include a-stereogenic C À Sb onds,t he synthesis of higher-substituted allylic thioethers [10,11] and sulfones [12,13] could be seen as an important synthetic tool in organic chemistry [14,15] and drug synthesis.F urthermore, a-stereogenic allylic Z-configured thioethers showed activity against allergic asthma and other immediate hypersensitivity diseases. [16] Thus we were curious to see whether we could transfer our initial methodology to 1,3-disubstituted allenes.H erein we describe the first rhodium-catalyzed, highly Z-selective and, if desired, asymmetric, hydrothiolation of 1,3-disubstituted allenes.A fter optimization of the reaction conditions using naphthalene-2-thiol and nona-4,5-diene with addition of p-toluenesulfonic acid (PTSA), the sulfone 1 was obtained in 80 %y ield and 91:9 Z selectivity (Table 1). [17][18][19] Furthermore,weinvestigated the scope of different aromatic thiols for this hydrothiolation.…”

A Facile One-Pot Preparation of Alkyl Aminoaryl Sulfides for the Synthesis of GW7647 as an Agonist of Peroxisome Proliferator-Activated Receptor α

“…However, despite the importance of alkyl aminoaryl sulfides, streamlined methods for synthesizing these sulfides have not been fully investigated. Generally, most alkyl aminoaryl sulfides are prepared by a substitution reaction of electrophiles, such as organic halides and/or epoxides, etc., with alkali metal aminoaryl thiolate which is generated from 2-, 3-, and/or 4-aminothiophenol in the presence of strong alkaline bases . Although these classical methods result in good yields, there is limited availability of aminothiophenol derivatives from commercial sources.…”