Recent Advances in Neurokinin Receptor Antagonists

Ohnmacht, Cyrus J.; Rumsey, William L.; Shenvi, Ashok B.

doi:10.1016/s0065-7743(08)61073-8

Cited by 1 publication

(1 citation statement)

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“…Modification of the compound properties may also provide a way to improve tolerability. Many basic amine-based NK 1 antagonists have previously been reported, 7 but few nonbasic ones were found in literature. Therefore, our efforts have focused on nonbasic NK 1 antagonists in the hope of improving brain penetration and reducing off-target activities associated with basic amine functionalities.…”

Section: Introductionmentioning

confidence: 99%

Potent, Brain-Penetrant, Hydroisoindoline-Based Human Neurokinin-1 Receptor Antagonists

et al. 2009

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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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Section: Introductionmentioning

confidence: 99%