Trisubstituted pyridine leukotriene B4 receptor antagonists: synthesis and structure-activity relationships

Abstract

A series of trisubstituted pyridines have been prepared that exhibit in vitro leukotriene B4 (LTB4, 1) receptor antagonist activity. Previous disubstituted pyridines from these labs showed high affinity for the LTB4 receptor but demonstrated agonist activity in functional assays (e.g., 2, Ki = 1 nM). Compound 4, the initial lead compound of this new series, showed only modest affinity by comparison (Ki = 282 nM); however, 4 was a receptor antagonist with no demonstrable agonist activity up to 10 microM. Subsequent modifications of the lipid tail and aryl head group region led to the discovery of aniline 50 (SB 201146). This compound, also free of agonist activity, possesses high affinity for the LTB4 receptor (Ki = 4.7 nM).

Involvement of cysteinyl leukotrienes in airway smooth muscle cell DNA synthesis after repeated allergen exposure in sensitized Brown Norway rats

“…1.13.11.34) inhibitor, SB 210661 ( McLoughlin et al ., 1998 ), and a cysteinyl leukotriene (CysLT 1 ) receptor antagonist, pranlukast (SB 205312, ONO‐1078) ( Obata et al ., 1992 ; Fujiwara et al ., 1993 ; Taki et al ., 1994 ), in order to evaluate the role of CysLT in bronchial responsiveness and airway wall remodelling. In addition, the potential contribution of another 5‐LO product, leukotriene B 4 , in these processes has been studied using a specific LTB 4 (BLT) receptor antagonist, SB 201146 ( Daines et al ., 1993 , 1996 ).…”

Synthesis of substituted 2H-benzo[e]indazole-9-carboxylate as a potent antihyperglycemic agent that may act through IRS-1, Akt and GSK-3β pathways

“…The ring transformation proceeded via Michael addition of the conjugate base of 4 to the lactones 3a-h at position 6 followed by intramolecular cyclization and subsequent loss of CO 2 . Oxidation of the methylthio group to the methylsulfonyl group was achieved in 58-75% yield by stirring an equimolar mixture of 5e and 5g with meta-chloroperbenzoic acid (m-CPBA) 49 in dry dichloromethane for 30-60 minutes at ambient temperature to afford the methyl 8-(methylsulfonyl)-2-phenyl-6-aryl-4,5dihydro-2H-benzoije]indazole-9-carboxylates 6a and 6b (Scheme 1). All the new synthesized derivatives of 2Hbenzoije]indazole-9-carboxylates (5a-c, e, f, h and 6a, b) were characterized by spectroscopic analyses.…”

Dual Colorimetric and Fluorescent Authentication Based on Semiconducting Polymer Dots for Anticounterfeiting Applications

“…PPE, PFBT ( M n ∼ 17 000–23 000), and PSMA ( M n ∼ 1900, 25% maleic anhydride) polymers were purchased from Sigma-Aldrich while PFBTDBT ( M n ∼ 12 000) was synthesized according to our previously published work . Spiropyran derivatives were synthesized according to previously published reports, ,, and thus, their synthetic procedures were not described herein. Other compounds were synthesized with modified procedures, and the appropriate literature was cited for each compound.…”

“…For the preparation of PSMA-SP(B), 2 μL of 2-butyl-1octanol was added in the reaction. 34,37 The detailed synthesis of Py-Bips has been reported previously. 2,3 Briefly, 0.1 g (0.29 mmol) of 3-(3,3,6′-trimethylspiro-[indoline-2,2′-pyrano[3,2-b]pyridin]-1-yl)propan-1-ol was dissolved in 5 mL of dry THF, and then, 0.2 mL (3.2 mmol) of iodomethane was added dropwise.…”