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4-(Pyrrolidinyl)methoxybenzoic Acid Derivatives as a Potent, Orally Active VLA-4 Antagonist

2006; Pharmaceutical Society of Japan; Volume: 54; Issue: 11 Linguagem: Inglês

10.1248/cpb.54.1515

1347-5223

Jun Chiba, Shin Iimura, Yoshiyuki Yoneda, Yuichi Sugimoto, Takao Horiuchi, Fumito Muro, Yuichi Ochiai, Tomomi Ogasawara, Masao Tsubokawa, Yutaka Iigou, Gensuke Takayama, Tomoe Taira, Yoshimi Takata, Mika Yokoyama, Tohru Takashi, Atsushi Nakayama, Nobuo Machinaga,

Neuropeptides and Animal Physiology

A novel series of benzoic acid derivatives as VLA-4 antagonists were synthesized. Optimization, focusing on activity and lipophilicity needed for cell permeability, resulted in the identification of 15b and 15e with good activity (IC50 = 1.6 nM each) and moderate lipophilicity (Log D = 2.0, 1.8). Furthermore, 15e demonstrated efficacy in murine asthma model by an oral dose of 30 mg/kg.