Optimization of imidazole 5-lipoxygenase inhibitors and selection and synthesis of a development candidate |
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| Authors: | Mano Takashi Stevens Rodney W Ando Kazuo Kawai Makoto Kawamura Kiyoshi Nakao Kazunari Okumura Yoshiyuki Okumura Takako Sakakibara Minoru Miyamoto Kimitaka Tamura Tetsuya |
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| Affiliation: | Pfizer Global Research and Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2393, Japan. Takashi.Mano@pfizer.com |
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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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