CCR1 antagonists: what have we learned from clinical trials.
The identification of chemokines and their receptors as potent mediators of leukocyte infiltration raised interest in the potential role of these proteins on disease pathogenesis. This is exemplified by the chemokine receptor, CCR1, which has been shown to be up-regulated in a number of human diseases, the implications of which have been suggested by animal models where inhibition of CCR1 or its ligands have shown beneficial effects. These data support the possibility that a CCR1 antagonist will provide therapeutic benefit to patients with inflammatory diseases. Over the last several years, several of these antagonists entered clinical trials, including CP-481,715 (Pfizer) and MLN3897 (Millennium) for rheumatoid arthritis, BX471 (Berlex / Scherring AG) for multiple sclerosis, and AZD-4818 (Astra-Zeneca) for COPD. This review will describe the evidence that supported the role of CCR1 in these diseases, the results from clinical trials, and provide perspectives on what has been learned from these trials for potential application / consideration to other studies with chemokine receptor antagonists.
Pfizer Global Research and Development,Eastern Point Road,Groton, CT 06340, USA. Ronald.P.Gladue@Pfizer.com
Ronald P
RP
Gladue
Matthew F
MF
Brown
Samuel H
SH
Zwillich
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008024:Ligands; D054389:Receptors, CCR1