Chiral Brønsted Acid Catalyzed Cascade Alcohol Deprotection and Enantioselective Cyclization.

The protection-deprotection sequence is vital to organic synthesis. Here, we describe a novel catalytic cascade where a chiral Brønsted acid selectively removes ether protecting groups and catalyzes intramolecular cyclization in one pot. We tested three model substrates from our previous work and investigated the rate of deprotection through gas chromatography (GC) studies. This work builds on our stereoselective synthesis of lactones by streamlining our synthesis. It also opens the door for additional investigations into other catalytic cascade reactions using chiral Brønsted acid catalysts.

Evaluation of the effects of the weak CYP3A inhibitors atorvastatin and ethinyl estradiol/norgestimate on lomitapide pharmacokinetics in healthy subjects.

Lomitapide is a microsomal triglyceride transfer protein inhibitor approved as an adjunctive treatment for adult patients with homozygous familial hypercholesterolemia. Lomitapide is extensively metabolized via cytochrome P450 3A (CYP3A) and is a weak CYP3A inhibitor. Two phase 1 open-label, randomized (1:1), 2-arm drug interaction studies in healthy subjects assessed the effects of atorvastatin and ethinyl estradiol (EE)/norgestimate, both weak CYP3A inhibitors, on lomitapide pharmacokinetics with staggered (separated by 12 hours) or simultaneous administration. All subjects received a single dose of lomitapide (20 mg) in the evening on day 1. Atorvastatin (80 mg once daily, n = 32) or EE/norgestimate (0.035/0.25 mg once daily, n = 32) dosing was initiated on days 11 or 8, respectively, with evening (arm 1) or morning (arm 2) dosing; at steady state (days 15 or 22), a single lomitapide dose was administered; CYP3A inhibitor dosing continued for 6 days. Blood samples for pharmacokinetic analysis were taken until 168 hours postdose. With atorvastatin, lomitapide exposure was increased by approximately 2-fold and 1.3-fold, respectively, with simultaneous and staggered administration, respectively. Simultaneous and staggered EE/norgestimate and lomitapide administration resulted in an approximately 1.3-fold increase in lomitapide exposure. Reductions in lomitapide dose may be required for some patients when administered concomitantly with a weak CYP3A inhibitor.