title: 4-[5-Fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]phenyl]-3,4,5,6- tetrahydro-2H-pyran-4-carboxamide, an orally active inhibitor of 5-lipoxygenase with improved pharmacokinetic and toxicology characteristics.
abstract: Described herein are structure-activity relationships (SARs) of 4-[5-fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]-phenyl]-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (1, CJ-12,918), an imidazole 5-lipoxygenase (5-LO) inhibitor. When 1 was tested in preclinical studies, cataract formation was observed in rats; however, this compound was metabolized extensively in vivo and showed low systemic exposure. To eliminate this side effect and enhance bioavailability, structural modification was focused on replacing the methoxy group of 1 by modulating lipophilicity (i.e., predicted log D at pH 7.4). The SARs led to the discovery of 4-[5-fluoro-3-[4-(2-methyl-1H-imidazol-1-yl)benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (10, CJ-13,454), which was less lipophilic by 1.2 log D units and showed in vivo potency (ED(50) = 4-9 mg/kg) equipotent to 1. Enhanced metabolic stability resulted in fewer in vivo metabolites, as well as improved bioavailability and a better toxicological profile. Thus, 10 was found to be a more practical lead for an orally active 5-LO inhibitor.
authors.affiliation: Pfizer Global Research and Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2393, Japan. Takashi.Mano@japan.pfizer.com
authors.forename: Takashi
authors.initials: T
authors.lastname: Mano
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Okumura
authors.forename: Minoru
authors.initials: M
authors.lastname: Sakakibara
authors.forename: Takako
authors.initials: T
authors.lastname: Okumura
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tamura
authors.forename: Kimitaka
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Rodney W
authors.initials: RW
authors.lastname: Stevens
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002386:Cataract / Q000139:chemically induced; D000882:Haplorhini; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000633:toxicity; D016859:Lipoxygenase Inhibitors; D008297:Male; D051379:Mice; D011714:Pyrans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: C482800:4-(5-fluoro-3-(4-(2-methyl-1H-imidazol-1-yl)benzyloxy)phenyl)-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide; D007093:Imidazoles; D016859:Lipoxygenase Inhibitors; D011714:Pyrans