Optimization of imidazole 5-lipoxygenase inhibitors and selection and synthesis of a development candidate

…, M Kawai, K Kawamura, K Nakao, Y Okumura…

Index: Mano, Takashi; Stevens, Rodney W.; Ando, Kazuo; Kawai, Makoto; Kawamura, Kiyoshi; Nakao, Kazunari; Okumura, Yoshiyuki; Okumura, Takako; Sakakibara, Minoru; Miyamoto, Kimitaka; Tamura, Tetsuya Chemical and Pharmaceutical Bulletin, 2005 , vol. 53, # 8 p. 965 - 973

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Citation Number: 18

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 ...