David C. Boyles

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.

Novel, base-promoted reaction of N-alkoxycarbonyl-O-(halosubstituted 4-nitrophenyl)-hydroxylamines

Abstract This paper describes base-promoted reactions of N -alkoxycarbonyl- O -(nitrophenyl)hydroxylamines which contain a halogen attached to the aromatic ring. The reaction is promoted under mild conditions (NaHCO 3 or K 2 CO 3 ) and provides the N -alkoxycarbonyl- N -hydroxyaniline. In a crossover experiment, some scrambling was observed which suggests that the reaction is inter- and intramolecular in nature. N -Boc-(2,6-di-Cl-4-NO 2 -phenyl)hydroxylamine was also found to N -Boc aminate Bn 2 NH to form the protected hydrazine in modest yield.