2. Academic Validation
  3. Potent, brain-penetrant, hydroisoindoline-based human neurokinin-1 receptor antagonists

Potent, brain-penetrant, hydroisoindoline-based human neurokinin-1 receptor antagonists

  • J Med Chem. 2009 May 14;52(9):3039-46. doi: 10.1021/jm8016514.
Jinlong Jiang 1,  Jaime L Bunda,  Geoge A Doss,  Gary G Chicchi,  Marc M Kurtz,  Kwei-Lan C Tsao,  Xinchun Tong,  Song Zheng,  Alana Upthagrove,  Koppara Samuel,  Richard Tschirret-Guth,  Sanjeev Kumar,  Alan Wheeldon,  Emma J Carlson,  Richard Hargreaves,  Donald Burns,  Terence Hamill,  Christine Ryan,  Stephen M Krause,  WaiSi Eng,  Robert J DeVita,  Sander G Mills
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA. jinlong_jiang@merck.com
PMID: 19354254 DOI: 10.1021/jm8016514
Abstract

3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one (17) is a high affinity, brain-penetrant, hydroisoindoline-based neurokinin-1 (NK(1)) receptor antagonist with a long central duration of action in preclinical species and a minimal drug-drug interaction profile. Positron emission tomography (PET) studies in rhesus showed that this compound provides 90% NK(1) receptor blockade in rhesus brain at a plasma level of 67 nM, which is about 10-fold more potent than aprepitant, an NK(1) antagonist marketed for the prevention of chemotherapy-induced and postoperative nausea and vomiting (CINV and PONV). The synthesis of this enantiomerically pure compound containing five stereocenters includes a Diels-Alder condensation, one chiral separation of the cyclohexanol intermediate, an ether formation using a trichloroacetimidate intermediate, and bis-alkylation to form the cyclic amine.

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