4-(Pyrrolidinyl)methoxybenzoic acid derivatives as a potent, orally active VLA-4 antagonist.
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.
Chiba
Jun
J
Medicinal Chemistry Research Laboratory, Daiichi Pharmaceutical, Co., Ltd., Tokyo, Japan. chiba2mk@daiichipharm.co.jp
Iimura
Shin
S
Yoneda
Yoshiyuki
Y
Sugimoto
Yuichi
Y
Horiuchi
Takao
T
Muro
Fumito
F
Ochiai
Yuichi
Y
Ogasawara
Tomomi
T
Tsubokawa
Masao
M
Iigou
Yutaka
Y
Takayama
Gensuke
G
Taira
Tomoe
T
Takata
Yoshimi
Y
Yokoyama
Mika
M
Takashi
Tohru
T
Nakayama
Atsushi
A
Machinaga
Nobuo
N
D000284:Administration, Oral; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D001565:Benzoates / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D002463:Cell Membrane Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D062425:Hydroxybenzoate Ethers; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000166:cytology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008968:Molecular Conformation; D011759:Pyrrolidines / Q000737:chemistry*; D011760:Pyrrolidinones / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C516633:4-(Pyrrolidinyl)methoxybenzoic acid; D001565:Benzoates; D062425:Hydroxybenzoate Ethers; D039041:Integrin alpha4beta1; D011759:Pyrrolidines; D011760:Pyrrolidinones