(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

Abstract

(E)-3-[[[[6-(2-Carboxyethenyl)-5-[[8-(4- methoxyphenyl)octyl]oxy]-2-pyridinyl]methyl]thio]methyl]benzoic acid (11, SB 201993) is a novel, potent LTB4 receptor antagonist. Compound 11 arose from a structure-activity study of a series of trisubstituted pyridines that demonstrated LTB4 receptor antagonist activity. The placement of an additional methylene unit in the sulfur containing chain linking the pyridine and benzoic acid moieties of lead compound 8 (K(i) = 80 nM) resulted in a greater than 10-fold increase in receptor affinity. Additionally, in this new series of compounds, the oxidation state of the sulfur was found to be critical to the activity, i.e., the sulfoxide and sulfone showed substantially lower affinity for the LTB4 receptor. Compound 11 competitively inhibits the binding of [3H]LTB4 to LTB4 receptors on human polymorphonuclear leukocytes with a Ki of 7.1 nM and blocks both the LTB4-induced calcium mobilization and the LTB4-induced degranulation responses in these cells with IC50 values of 131 and 271 nM, respectively. Compound 11 demonstrated oral LTB4 antagonist activity as well as topical antiinflammatory activity in the mouse.

(E)-3-[6-[[(2,6-Dichlorophenyl)thio]methyl]-3-(2-phenylethoxy)-2-pyridinyl]-2- propenoic Acid: A High-Affinity Leukotriene B4 Receptor Antagonist with Oral Antiinflammatory Activity

“…Compounds 8 , 9 , 13 , and 14 were synthesized according to procedures previously described . The phenylethyl-containing compounds of the present study were synthesized according to Scheme (illustrated for compound 3 ).…”

“…Previously, we reported the identification of the novel high-affinity LTB 4 receptor antagonists SB 201146 ( 1 , K i = 4.7 nM) and SB 201993 ( 2 , K i = 7.1 nM) …”

Shedding Some Light on Crystallization Issues: Lecture Transcript from the First International Symposium on Aspects of Polymorphism and Crystallization − Chemical Development Issues1

“…The two case studies presented in this lecture involve compounds that emerged from SB's Inflammation and Tissue Repair programme and are LTB 4 antagonists (see Figure ). Since leukotrienes have been implicated in the formation of psoriatic plaque, SB-201993 and SB-209247 were being developed for the treatment of psoriasis. − SB-201993 did not show oral bioavailability and thus was being developed solely as a topical agent where a solution/suspension of the active component in a paraffin wax would be applied directly to the affected skin. As some relief from psoriasis occurs on exposure to sunlight, it was important that the topical formulations showed good light stability.…”

Εξαγωγή Και Μελέτη Ποσοτικών Σχέσεων Δομής-Δράσης (QSAR) Ενώσεων Με Δράση Κατά Των Σερινοπρωτεασών. Σύνθεση Και Φαρμακοχημική Μελέτη Κουμαρινικών Παραγώγων Με Πιθανή Βιολογική Δράση Κατά Των Σερινοπρωτεασών Και Της Φλεγμονής

“…$ , & [Müller 1994]. # LTB 4 , [Müller 1994, Daines et al 1994]. # LTC 4 , LTD 4 LTE 4 [Satoh et al 1994].…”