benzofurans and Pulmonary-Disease--Chronic-Obstructive

Talniflumate, an anti-inflammatory molecule that was originally developed by Laboratorios Bago, is currently being developed by Genaera as a mucoregulator for the treatment of cystic fibrosis, chronic obstructive pulmonary disease and asthma. Phase I trials with talniflumate had been completed by August 2001, and phase II trials were underway in Ireland for the treatment of cystic fibrosis.

Topics: Animals; Anti-Inflammatory Agents; Asthma; Benzofurans; Chloride Channels; Clinical Trials as Topic; Cystic Fibrosis; Expectorants; Humans; Pulmonary Disease, Chronic Obstructive; Pyridines; Sinusitis; Structure-Activity Relationship

Cognitive impairment is a common finding in patients with chronic obstructive pulmonary disease (COPD), but little attention has been focused on therapeutic intervention for this complication. Chronic intermittent hypoxia hypercapnia (CIHH) exposure is considered to be responsible for the pathogenesis of COPD. Dl-3n-Butylphthalide (NBP), extracted from Apium graveolens Linn, has displayed a broad spectrum of neuroprotective properties. Our study aimed to investigate the potential of NBP on CIHH-induced cognitive deficits. The cognitive function of rats after CIHH exposure was evaluated by the Morris water maze, which showed that the NBP treated group performed better in the navigation test. NBP activated BDNF and phosphorylated CREB, the both are responsible for neuroprotection. Additionally, NBP decreased CIHH induced apoptosis. Moreover, NBP further induced the expression of HIF-1α, accompanied by the up-regulation of the autophagy proteins Bnip3, Beclin-1 and LC3-II. Finally, NBP also reversed the decreased expression of SIRT1 and PGC-1α, but the expression of Tfam, Cox II and mtDNA remained unchanged. These results suggested that the neuroprotective effects of NBP under CIHH condition possibly occurred through the inhibition of apoptosis, promotion of hypoxia-induced autophagy, and activation of the SIRT1/PGC-1α signalling pathway, while stimulation of mitochondrial biogenesis may not be a characteristic response.

Topics: Animals; Apoptosis; Benzofurans; Brain-Derived Neurotrophic Factor; Drug Evaluation, Preclinical; Hypercapnia; Hypoxia, Brain; Male; Maze Learning; Memory; Mitochondrial Turnover; Neuroprotective Agents; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Sirtuin 1; Transcription Factors

Matrix metalloprotease 12 plays a significant role in airway inflammation and remodeling. Increased expression and production of MMP-12 have been found in the lung of human COPD patients. MMP408 (14), a potent and selective MMP-12 inhibitor, was derived from a potent matrix metalloprotease 2 and 13 inhibitor via lead optimization and has good physical properties and bioavailability. The compound blocks rhMMP-12-induced lung inflammation in a mouse model and was advanced for further development for the treatment of COPD.

Topics: Animals; Benzofurans; Biological Availability; Haplorhini; Humans; In Vitro Techniques; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred C57BL; Models, Molecular; Pneumonia; Pulmonary Disease, Chronic Obstructive; Rats; Recombinant Proteins; Sheep; Species Specificity; Stereoisomerism; Structure-Activity Relationship; Sulfonamides