Xue-Min Cheng

Discovery of novel hepatoselective HMG-CoA reductase inhibitors for treating hypercholesterolemia: a bench-to-bedside case study on tissue selective drug distribution.

The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (26) as a candidate for treating hypercholesterlemia. Clinical evaluation of 26 (PF-03491165), as well as the previously reported 2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors.

Synthesis of benzocycloheptenones by 1,3-dipolar additions of 2-(1,3-benzodioxol-5-ylmethyl)-4-hydroxy-3-methoxy-carbonylisoquinolin-2-ium chloride with dipolarophiles

The addition of thionyl chloride to dihydroisoquinolines affords isoquinolinium chlorides which are readily converted to the corresponding ylides upon treatment with sodium hydrogen carbonate. These ylides undergo facile 1,3-dipolar additions with dimethyl acetylenedicarboxylate, maleic anhydride and acrylonitrile to afford the corresponding benzocycloheptenone cycloadduct.