Optimization of Imidazole 5-Lipoxygenase Inhibitors and Selection and Synthesis of a Development Candidate

Takashi Mano; Rodney W. Stevens; Kazuo Ando; Makoto Kawai; Kiyoshi Kawamura; Kazunari Nakao; Yoshiyuki Okumura; Takako Okumura; Minoru Sakakibara; Kimitaka Miyamoto; Tetsuya Tamura

doi:10.1248/cpb.53.965

Regular Articles

Optimization of Imidazole 5-Lipoxygenase Inhibitors and Selection and Synthesis of a Development Candidate

Takashi Mano, Rodney W. Stevens, Kazuo Ando, Makoto Kawai, Kiyoshi Kawamura, Kazunari Nakao, Yoshiyuki Okumura, Takako Okumura, Minoru Sakakibara, Kimitaka Miyamoto, Tetsuya Tamura

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Keywords: lipoxygenase, inhibitor, structure–activity relationship, leukotriene, unsymmetric thioether

JOURNAL FREE ACCESS

2005 Volume 53 Issue 8 Pages 965-973

DOI https://doi.org/10.1248/cpb.53.965

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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.

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