Potent, brain-penetrant, hydroisoindoline-based human neurokinin-1 receptor antagonists.
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.
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA. jinlong_jiang@merck.com
Jinlong
J
Jiang
Jaime L
JL
Bunda
Geoge A
GA
Doss
Gary G
GG
Chicchi
Marc M
MM
Kurtz
Kwei-Lan C
KL
Tsao
Xinchun
X
Tong
Song
S
Zheng
Alana
A
Upthagrove
Koppara
K
Samuel
Richard
R
Tschirret-Guth
Sanjeev
S
Kumar
Alan
A
Wheeldon
Emma J
EJ
Carlson
Richard
R
Hargreaves
Donald
D
Burns
Terence
T
Hamill
Christine
C
Ryan
Stephen M
SM
Krause
WaiSi
W
Eng
Robert J
RJ
DeVita
Sander G
SG
Mills
D000284:Administration, Oral; D000818:Animals; D000077608:Aprepitant; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D054833:Isoindoles / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008253:Macaca mulatta; D009025:Morpholines / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D054833:Isoindoles; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D000077608:Aprepitant