title: Optimization of imidazole 5-lipoxygenase inhibitors and selection and synthesis of a development candidate.
abstract: Structural modification of imidazole 5-lipoxygenase (5-LO) inhibitors for optimizing inhibitory potency, pharmacokinetic behavior and toxicity (ocular) profile led to 4-{3-[4-(2-methyl-1H-imidazol-1-yl)phenylthio]}phenyl-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide (6) with no observable ocular toxicity. The orally active and safe imidazole 5-LO inhibitor 6 was selected as a clinical candidate and advanced to clinical studies. An improved synthesis of 6 is also discussed.
authors.affiliation: Pfizer Global Research and Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2393, Japan. Takashi.Mano@pfizer.com
authors.forename: Takashi
authors.initials: T
authors.lastname: Mano
authors.forename: Rodney W
authors.initials: RW
authors.lastname: Stevens
authors.forename: Kazuo
authors.initials: K
authors.lastname: Ando
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawai
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Kawamura
authors.forename: Kazunari
authors.initials: K
authors.lastname: Nakao
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Okumura
authors.forename: Takako
authors.initials: T
authors.lastname: Okumura
authors.forename: Minoru
authors.initials: M
authors.lastname: Sakakibara
authors.forename: Kimitaka
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000818:Animals; D005260:Female; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D009682:Magnetic Resonance Spectroscopy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007093:Imidazoles; D016859:Lipoxygenase Inhibitors