Evaluation of a series of bicyclic CXCR2 antagonists.
The CXCR2 SAR of a series of bicyclic antagonists such as the 2-aminothiazolo[4,5-d]pyrimidine 3b was investigated by systematic variation of the fused pyrimidine-based heterocyclic cores. Replacement of the aminothiazole ring with a 2-thiazolone alternative led to a series of thiazolo[4,5-d]pyrimidine-2(3H)-one antagonists with markedly improved biological and pharmacokinetic properties, which are suitable pharmacological tools to probe the in vivo effects of CXCR2 antagonism combined with the associated CCR2 activity.
Walters
Iain
I
Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, United Kingdom. iain.walters@astrazeneca.com
Austin
Caroline
C
Austin
Rupert
R
Bonnert
Roger
R
Cage
Peter
P
Christie
Mark
M
Ebden
Mark
M
Gardiner
Stuart
S
Grahames
Caroline
C
Hill
Steven
S
Hunt
Fraser
F
Jewell
Robert
R
Lewis
Shirley
S
Martin
Iain
I
David Nicholls
David Robinson
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004353:Drug Evaluation, Preclinical; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D011743:Pyrimidines; D023063:Receptors, Interleukin-8B