2. Academic Validation
  3. 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

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

  • J Med Chem. 2013 Jul 25;56(14):5940-8. doi: 10.1021/jm400751p.
Andrew J Kassick 1,  Jinlong Jiang,  Jaime Bunda,  David Wilson,  Jianming Bao,  Huagang Lu,  Peter Lin,  Richard G Ball,  George A Doss,  Xinchun Tong,  Kwei-Lan C Tsao,  Hong Wang,  Gary Chicchi,  Bindhu Karanam,  Richard Tschirret-Guth,  Koppara Samuel,  Donald F Hora,  Sanjeev Kumar,  Maria Madeira,  Waisi Eng,  Richard Hargreaves,  Mona Purcell,  Liza Gantert,  Jacquelyn Cook,  Robert J DeVita,  Sander G Mills
Affiliations

Affiliation

  • 1 Discovery Chemistry, ‡In Vitro Pharmacology, §Drug Metabolism, and ∥Laboratory Animal Resources, Merck Research Laboratories, Merck & Co. , Rahway, New Jersey 07065, United States.
PMID: 23808489 DOI: 10.1021/jm400751p
Abstract

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.

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