197144-65-3

Upstream product

• 108-95-2 phenol 
• 539-88-8 4-oxopentanoic acid ethyl ester 
• 126-00-1 4,4-bis(4-hydroxyphenyl)valeric acid 
• 7297-85-0 4-hydroxy-γ-(4-hydroxyphenyl)-γ-methyl-benzenebutanoic acid methyl ester 
• 3747-74-8 2-(chloromethyl)quinoline monohydrochloride 

Relevant academic research and scientific papers

Symmetrical bis(heteroarylmethoxyphenyl)alkylcarboxylic acids as inhibitors of leukotriene biosynthesis

Symmetrical bis(quinolylmethoxyphenyl)alkylcarboxylic acids were investigated as inhibitors of leukotriene biosynthesis and 4,4-bis(4-(2-quinolylmethoxy)phenyl)pentanoic acid sodium salt (47·Na) met our design parameters for a drug candidate (ABT-080). This compound was readily synthesized in three steps from commercially available diphenolic acid. Against intact human neutrophils, 47·Na inhibited ionophore-stimulated LTB4 formation with an IC50 = 20 nM. In zymosan-stimulated mouse peritoneal macrophages producing both LTC4 and PGE2, 47·Na showed 9000-fold selectivity for inhibition of LTC4 (IC50 = 0.16 nM) over PGE2 (IC50 = 1500 nM). Preliminary pharmacokinetic evaluation in rat and cynomolgus monkey demonstrated good oral bioavailability and elimination half-lives of 9 and 5 h, respectively. Pharmacological evaluation of leukotriene inhibition with oral dosing was demonstrated in a rat pleural inflammation model (ED50 = 3 mg/kg) and a rat peritoneal passive anaphylaxis model (LTB4, ED50 = 2.5 mg/kg; LTE4, ED50 = 1.0 mg/kg). In a model of airway constriction induced by antigen challenge in actively sensitized guinea pigs, 47·Na dosed orally blocked bronchoconstriction with an ED50 = 0.4 mg/kg, the most potent activity we have observed for any leukotriene inhibitor in this model. The mode of inhibitory action of 47·Na occurs at the stage of 5-lipoxygenase biosynthesis as it blocks both leukotriene pathways leading to LTB4 and LTC4 but not PGH2 biosynthesis. However, 47·Na does not inhibit 5-lipoxygenase catalysis in a broken cell enzyme assay; therefore it is likely that 47·Na acts as a FLAP inhibitor.

Non-symmetrical bis-heteroarylmethoxyphenylalkyl carboxylates as inhibitors of leukotriene biosynthesis

Compounds having the formula STR1 wherein W and Y are independently selected from optionally substituted quinolyl, optionally substituted benzothiazolyl, optionally substituted benzoxazolyl, optionally substituted benzimidazolyl, optionally substituted quinoxalyl, and optionally substituted naphthyl with the proviso that W and Y are not simultaneously the same substituent; R1 and R2 are independently hydrogen, alkyl, haloalkyl, alkoxy, or halogen; R3 is hydrogen or alkyl; X is absent or is alkylene, alkenylene, or alkynylene; and M is selected from (a) a pharmaceutically acceptable metabolically cleavable group, (b) --OR4 wherein R4 is hydrogen or alkyl; and (c) --NR5 R6 wherein R5 and R6 are independently selected from hydrogen, alkyl, hydroxy and alkoxy are disclosed. These compounds inhibit leukotriene biosynthesis and are useful in the treatment of allergic and inflammatory disease states.