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 toxicit...

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Veröffentlicht in:	Chemical & Pharmaceutical Bulletin 2005, Vol.53(8), pp.965-973
Hauptverfasser:	Mano, Takashi, Stevens, Rodney W., Ando, Kazuo, Kawai, Makoto, Kawamura, Kiyoshi, Nakao, Kazunari, Okumura, Yoshiyuki, Okumura, Takako, Sakakibara, Minoru, Miyamoto, Kimitaka, Tamura, Tetsuya
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Female Imidazoles - chemical synthesis Imidazoles - chemistry Imidazoles - pharmacokinetics Imidazoles - pharmacology Imidazoles - toxicity inhibitor leukotriene lipoxygenase Lipoxygenase Inhibitors - chemical synthesis Lipoxygenase Inhibitors - chemistry Lipoxygenase Inhibitors - pharmacokinetics Lipoxygenase Inhibitors - pharmacology Lipoxygenase Inhibitors - toxicity Magnetic Resonance Spectroscopy Rats Rats, Sprague-Dawley structure–activity relationship unsymmetric thioether
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Zusammenfassung:	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.
ISSN:	0009-2363 1347-5223
DOI:	10.1248/cpb.53.965