Development of cell adhesion molecule antagonists as therapeutics for asthma and COPD.
Airway inflammation is a hallmark of respiratory diseases such as asthma and chronic obstructive pulmonary disease. Cell adhesion molecules play critical roles in the recruitment and migration of cells to sites of inflammation. Not surprisingly, these receptors have garnered the attention of the pharmaceutical industry as targets for the development of drugs to treat inflammatory and autoimmune diseases. Although several potential cell adhesion targets exist, development of compounds for pulmonary indications has centered around the selectins and the integrin VLA-4. In vitro and in vivo studies have implicated these receptors in the recruitment of inflammatory cells to the lung as well as to key cellular activation pathways. Several first generation compounds are currently in clinical development for asthma. Positive data from a phase II clinical trial using an inhaled formulation of a selectin antagonist has recently been reported. Initial results from clinical trials using first generation VLA-4 antagonists have been less promising but additional trials with more fully optimized compounds are underway. Results from these trials will provide insight into what the future holds for this exciting new class of drugs to treat pulmonary diseases.
Vanderslice
Peter
P
Department of Biology, Encysive Pharmaceuticals, 7000 Fannin, 19th Floor, Houston, TX 77030, USA. pvanderslice@encysive.com
Biediger
Ronald J
RJ
Woodside
Darren G
DG
Berens
Kurt L
KL
Holland
George W
GW
Dixon
Richard A F
RA
D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D001713:Biphenyl Compounds / Q000627:therapeutic use; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors*; D002626:Chemistry, Pharmaceutical; D002986:Clinical Trials as Topic; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors; D008358:Mannose / Q000031:analogs & derivatives; D008362:Mannosides / Q000627:therapeutic use; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D019087:Selectins / Q000187:drug effects
D001713:Biphenyl Compounds; D015815:Cell Adhesion Molecules; D039041:Integrin alpha4beta1; D008362:Mannosides; C459380:N-(2,6-dichlorobenzoyl)-4-(2',6'-bismethoxyphenyl)phenylalanine; D019087:Selectins; D010649:Phenylalanine; C108700:bimosiamose disodium; D008358:Mannose