Optimization of imidazole 5-lipoxygenase inhibitors and selection and synthesis of a development candidate.
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.
Mano
Takashi
T
Pfizer Global Research and Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2393, Japan. Takashi.Mano@pfizer.com
Stevens
Rodney W
RW
Ando
Kazuo
K
Kawai
Makoto
M
Kawamura
Kiyoshi
K
Nakao
Kazunari
K
Okumura
Yoshiyuki
Y
Okumura
Takako
T
Sakakibara
Minoru
M
Miyamoto
Kimitaka
K
Tamura
Tetsuya
T
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
D007093:Imidazoles; D016859:Lipoxygenase Inhibitors