Organic Synthesis, In Vivo Distribution And Pharmacokinetics Of Small Molecule Porcine CFTR Inhibitors

Cystic fibrosis (CF) is the most prevalent lethal autosomal recessive genetic disease in Caucasians. The most significant clinical symptom is recurrent lung infections and fibrosis that results in irreversible deterioration in lung function. CF is caused by the mutation of cystic fibrosis transmembrane conductance regulator (CFTR), which is a 3`,5`-cyclic monophosphate (cAMP)-regulated Cl- channel expressed primarily in airways, small intestine, and pancreas epithelial. More than 1300 CFTR mutations may lead to CF, andΔF508 mutation accounts for about 70% CF patients. Because of the complexibility and uncertainty of CF pathogenesis, there is still little effective therapy, average life time of CF patients is around 35. There are mainly two ways in CF pathogenesis study: CFTR specific blocker inhibition study andΔF508-CFTR transgenic and CFTR gene knocks mouse study. Due to the significant difference in physiological pattern of submucosal glands in airways, the transgenic and gene knocks mouse failed to display CF patients'lungs fibrosis sympotem. It's necessary to make mamalial CF model that mimic human CF sympotems. Pig is highly resemblance with human in anatomy physiological functions, which make it suitable for CF model. Previous study manifested that pig CFTR gene and protein has more than 90% identity to that of human beings. Two human CFTR specific blockers, CFTRinh-172 and GlyH101, were identified by using a cell-based fluorescence assay. The CFTR blockers may play roles in mammalian CF model construction. Our previous study got little succeed in making pig CF model with CFTRinh-172, poor solubility in aquous solution may account part of the reasons. GlyH101 which is also originally identified as human CFTR specific blocker but with a better solubility may provide new tool for CF animal construction.The present study was to established HPLC quantitification method of GlyH101, and system analysis dynamic distributionin of GlyH101 in a mouse model. A pig CFTR specific blocker was synthesized; structure and activity of the inhibitor were also systematically evaluated.