Synthesis and biological evaluation of benzoic acid derivatives as potent, orally active VLA-4 antagonists.
A series of benzoic acid derivatives was synthesized as VLA-4 antagonists. Introduction of chlorine or bromine into the 3-position on the central benzene of the diphenylurea portion as in lead compound 2 led to improvement in the pharmacokinetic properties. In particular, 12l demonstrated an acceptable plasma clearance and bioavailability in mice and rats as well as dogs (mice, CL=18.5 ml/min/kg,F=28%; rats, CL=5.2 ml/min/kg,F=36%; dogs, CL=3.6 ml/min/kg,F=55%). Additionally, 12l exhibited potent activity with an IC50 value of 0.51 nM and efficacy by oral administration at a dosage of 10 mg/kg in a rat pleurisy model.
Chiba
Jun
J
Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical, Co., Ltd, 16-13, Kitakasai 1-chome, Edogawa-ku, Tokyo 134-8630, Japan. chiba2mk@daiichipharm.co.jp
Iimura
Shin
S
Yoneda
Yoshiyuki
Y
Watanabe
Toshiyuki
T
Muro
Fumito
F
Tsubokawa
Masao
M
Iigou
Yutaka
Y
Satoh
Atsushi
A
Takayama
Gensuke
G
Yokoyama
Mika
M
Takashi
Tohru
T
Nakayama
Atsushi
A
Machinaga
Nobuo
N
D000284:Administration, Oral; D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D007249:Inflammation / Q000188:drug therapy; D020128:Inhibitory Concentration 50; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D051379:Mice; D010599:Pharmacokinetics; D010998:Pleurisy / Q000188:drug therapy; D051381:Rats; D013329:Structure-Activity Relationship
D001565:Benzoates; D039041:Integrin alpha4beta1