Chiral morpholinone is an important building block in organic synthesis and a pharmacophore in medicinal chemistry. However, catalytic enantioselective methods for the construction of this N,O-heterocycle remain scarce. We report herein a chiral phosphoric acid-catalyzed enantioselective synthesis of C3-substituted morpholinones from aryl/alkylglyoxals and 2-(arylamino)ethan-1-ols. The reaction proceeds through a domino [4 + 2] heteroannulation followed by a 1,2-aryl/alkyl shift of the resulting cyclic α-iminium hemiacetals. It represents formally an unprecedented asymmetric aza-benzilic ester rearrangement reaction. A concise synthesis of L-742,694, a neurokinin-1 receptor antagonist, featuring this reaction is documented.

23 Jun 2014·Journal of Chemical Information and ModelingQ2 · CHEMISTRY

Pharmacophore Modeling, Virtual Screening, and in Vitro Testing Reveal Haloperidol, Eprazinone, and Fenbutrazate as Neurokinin Receptors Ligands

Q2 · CHEMISTRY

Article

Author: Sartori, Simone B. ; Krautscheid, Yvonne ; Stuppner, Hermann ; Schuster, Daniela ; Senning, Carl Johann Åke ; Singewald, Nicolas

Neurokinin receptors (NKRs) have been shown to be involved in many physiological processes, rendering them promising novel drug targets, but also making them the possible cause for side effects of several drugs. Aiming to answer the question whether the binding to NKRs could have a share in the side effects or even the desired effects of already licensed drugs, we generated a set of ligand-based common feature pharmacophore models based on the structural information about subtype-selective and nonselective NKR antagonists and screened an in-house database mainly composed of licensed drugs. The prospective pharmacological investigations of the virtual hits haloperidol, eprazinone, and fenbutrazate confirmed them to be NKR ligands in vitro. By the identification of licensed drugs as so far unknown NKR ligands, this study contributes to establishing an activity profile of the investigated compounds and confirms the presented pharmacophore models as useful tools for this purpose.

01 Sep 2006·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Cyclopentane-based human NK1 antagonists. Part 1: Discovery and initial SAR

Q4 · MEDICINE

Article

Author: Kwei-Lan Tsao ; Gary G. Chicchi ; D. Euan MacIntyre ; Laura C. Meurer ; Malcolm MacCoss ; Paul E. Finke ; Joseph M. Metzger ; Margaret A. Cascieri ; Sander G. Mills ; Sharon Sadowski ; Dorothy A. Levorse

An initial investigation of the novel cyclopentane scaffold 6 afforded low nanomolar human NK1 antagonists having enhanced water solubility properties compared to morpholine 1. A synthesis of this cyclopentane scaffold, having three contiguous chiral centers, and the unexpected determination that the 1,2-trans-2,3-trans-ring stereochemistry, as opposed to the cis-ether/phenyl configuration of the known structures 1-5, is optimal for this class of antagonist are described.

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Pain	Discovery	United States	Merck & Co., Inc.	-

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