Jianming Bao

A comparison of Diels-Alder catalysts generated from linear and vaulted biaryls and bromoborane-dimethylsulfide complex

Catalysts prepared from the vaulted biaryls 2 and 3 and bromoborane dimethylsulfide were compared with that generated from the linear biaryl 1 for their ability to provide enantioselective induction in the Diels-Alder reaction of cyclopentadiene and methacrolein. The fact that the S-enantiomers of 2 and 3 give opposite induction than the S-enantiomer of 1 and the fact that effective catalysts can not be generated from 1 and phenylboron dichloride suggests that the catalysts from 2 and 3 do not have the same structure as the C3-symmetrical catalyst 4 produced from 1.

2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one: A Potent Human NK1 Receptor Antagonist with Multiple Clearance Pathways

Hydroisoindoline 2 has been previously identified as a potent, brain-penetrant NK1 receptor antagonist with a long duration of action and improved profile of CYP3A4 inhibition and induction compared to aprepitant. However, compound 2 is predicted, based on data in preclinical species, to have a human half-life longer than 40 h and likely to have drug-drug-interactions (DDI), as 2 is a victim of CYP3A4 inhibition caused by its exclusive clearance pathway via CYP3A4 oxidation in humans. We now report 2-[(3aR,4R,5S,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethoxy}-4-(2-methylphenyl)octahydro-2H-isoindol-2-yl]-1,3-oxazol-4(5H)-one (3) as a next generation NK1 antagonist that possesses an additional clearance pathway through glucuronidation in addition to that via CYP3A4 oxidation. Compound 3 has a much lower propensity for drug-drug interactions and a reduced estimated human half-life consistent with once daily dosing. In preclinical species, compound 3 has demonstrated potency, brain penetration, and a safety profile similar to 2, as well as excellent pharmacokinetics.