Chem. Pharm. Bull.

Chem. Pharm. Bull., 53(8),965-973, August 2005

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, and Tetsuya TAMURA

Pfizer Global Research & Development, Nagoya Laboratories; 5-2 Taketoyo, Aichi 470-2393, Japan. * To whom correspondence should be addressed. e-mail: Takashi.Mano@pfizer.com

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.

Key words lipoxygenase; inhibitor; structure-activity relationship; leukotriene; unsymmetric thioether

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, and Tetsuya TAMURA

Pfizer Global Research & Development, Nagoya Laboratories; 5-2 Taketoyo, Aichi 470-2393, Japan. * To whom correspondence should be addressed. e-mail: Takashi.Mano@pfizer.com

Takashi MANO,^* Rodney W. STEVENS, Kazuo ANDO, Makoto KAWAI, Kiyoshi KAWAMURA, Kazunari NAKAO, Yoshiyuki OKUMURA, Takako OKUMURA, Minoru SAKAKIBARA, Kimitaka MIYAMOTO, and Tetsuya TAMURA