ABSTRACT
The potential use of SCD inhibitors for the chronic treatment of diabetes and dyslipidemia has been limited by preclinical adverse events associated with inhibition of SCD in skin and eye tissues. To establish a therapeutic window, we embarked on designing liver-targeted SCD inhibitors by utilizing molecular recognition by liver-specific organic anion transporting polypeptides (OATPs). In doing so, we set out to target the SCD inhibitor to the organ believed to be responsible for the therapeutic efficacy (liver) while minimizing its exposure in the tissues associated with mechanism-based SCD depletion of essential lubricating lipids (skin and eye). These efforts led to the discovery of MK-8245 (7), a potent, liver-targeted SCD inhibitor with preclinical antidiabetic and antidyslipidemic efficacy with a significantly improved therapeutic window.
Subject(s)
Acetates/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Hypolipidemic Agents/chemical synthesis , Liver/enzymology , Stearoyl-CoA Desaturase/antagonists & inhibitors , Tetrazoles/chemical synthesis , Acetates/chemistry , Acetates/pharmacology , Animals , Cell Line , Diffusion , Dogs , Female , Harderian Gland/metabolism , Hep G2 Cells , Hepatocytes/metabolism , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Hypolipidemic Agents/chemistry , Hypolipidemic Agents/pharmacology , In Vitro Techniques , Liver-Specific Organic Anion Transporter 1 , Macaca mulatta , Male , Mice , Mice, Inbred C57BL , Microsomes/metabolism , Organic Anion Transporters/metabolism , Organic Anion Transporters, Sodium-Independent/metabolism , Rats , Rats, Sprague-Dawley , Skin/metabolism , Solute Carrier Organic Anion Transporter Family Member 1B3 , Species Specificity , Structure-Activity Relationship , Tetrazoles/chemistry , Tetrazoles/pharmacology , Tissue DistributionABSTRACT
Salmonids utilize a unique, class II isoactin in slow skeletal muscle. This actin contains 12 replacements when compared with those from salmonid fast skeletal muscle, salmonid cardiac muscle and rabbit skeletal muscle. Substitutions are confined to subdomains 1 and 3, and most occur after residue 100. Depending on the pairing, the 'fast', 'cardiac' and rabbit actins share four, or fewer, substitutions. The two salmonid skeletal actins differ nonconservatively at six positions, residues 103, 155, 278, 281, 310 and 360, the latter involving a change in charge. The heterogeneity has altered the biochemical properties of the molecule. Slow skeletal muscle actin can be distinguished on the basis of mass, hydroxylamine cleavage and electrophoretic mobility at alkaline pH in the presence of 8 m urea. Further, compared with its counterpart in fast muscle, slow muscle actin displays lower activation of myosin in the presence of regulatory proteins, and weakened affinity for nucleotide. It is also less resistant to urea- and heat-induced denaturation. The midpoints of the change in far-UV ellipticity of G-actin versus temperature are approximately 45 degrees C ('slow' actin) and approximately 56 degrees C ('fast' actin). Similar melting temperatures are observed when thermal unfolding is monitored in the aromatic region, and is suggestive of differential stability within subdomain 1. The changes in nucleotide affinity and stability correlate with substitutions at the nucleotide binding cleft (residue 155), and in the C-terminal region, two parts of actin which are allosterically coupled. Actin is concluded to be a source of skeletal muscle plasticity.
