C(4)-alkyl substituted furanyl cyclobutenediones as potent, orally bioavailable CXCR2 and CXCR1 receptor antagonists.
A novel series of cyclobutenedione centered C(4)-alkyl substituted furanyl analogs was developed as potent CXCR2 and CXCR1 antagonists. Compound 16 exhibits potent inhibitory activities against IL-8 binding to the receptors (CXCR2 Ki=1 nM, IC(50)=1.3 nM; CXCR1 Ki=3 nM, IC(50)=7.3 nM), and demonstrates potent inhibition against both Gro-alpha and IL-8 induced hPMN migration (chemotaxis: CXCR2 IC(50)=0.5 nM, CXCR1 IC(50)=37 nM). In addition, 16 has shown good oral pharmacokinetic profiles in rat, mouse, monkey, and dog.
Chao
Jianhua
J
Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. jianhua.chao@spcorp.com <jianhua.chao@spcorp.com>
Taveras
Arthur G
AG
Chao
Jianping
J
Aki
Cynthia
C
Dwyer
Michael
M
Yu
Younong
Y
Purakkattle
Biju
B
Rindgen
Diane
D
Jakway
James
J
Hipkin
William
W
Fosetta
James
J
Fan
Xuedong
X
Lundell
Daniel
D
Fine
Jay
J
Minnicozzi
Michael
M
Phillips
Jonathan
J
Merritt
J Robert
JR
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004285:Dogs; D015195:Drug Design; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D006801:Humans; D020128:Inhibitory Concentration 50; D016209:Interleukin-8 / Q000737:chemistry; D007700:Kinetics; D051379:Mice; D051381:Rats; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*
D005663:Furans; D016209:Interleukin-8; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B