3-alkyl-6-chloro-2-pyrones: Selective inhibitors of pancreatic cholesterolesterase

A series of 3-alkyl-6-chloro-2-pyrones with cyclohexane rings tethered to t he S-position was synthesized. The tether ranged from 0 to 4 methylene unit s. Inhibition of pancreatic-cholesterol esterase by this series of pyrones was markedly dependent upon the length of the tether. Dissociation constant s as low as 25 nM were observed for 6-chloro-3-(1-ethyl-2-cyclohexyl)-2-pyr anone. This class of cholesterol esterase inhibitors functioned as simple c ompetitive inhibitors of substrate binding rather than as suicide substrate s or active site inactivators. Trypsin and chymotrypsin were not strongly i nhibited by this class of pyrones. Selectivities for cholesterol esterase w ere greater than 10(3). This is in contrast to 3-aryl-6-chloro-2-pyrones wh ich are nonselective, irreversible inactivators of serine hydrolases, Thus, replacement of the 3-aryl group by an appropriately tethered 3-alkyl ring can produce highly selective inhibitors of cholesterol esterase. A second s eries of halogen-containing esters was prepared in which cholesterol was es terified with alpha-haloacyl halides. These haloesters were simple substrat es of cholesterol esterase with no evidence of irreversible inactivation.