Quinazolinedione sulfonamides: A novel class of competitive AMPA receptor antagonists with oral activity Manuel Koller a,⇑ , Kurt Lingenhoehl b , Markus Schmutz b , Ivan-Toma Vranesic c , Joerg Kallen d , Yves P. Auberson a , David A. Carcache a , Henri Mattes a , Silvio Ofner a , David Orain a , Stephan Urwyler e a Novartis Institutes for BioMedical Research, Global Discovery Chemistry, 4002 Basel, Switzerland b Novartis Institutes for BioMedical Research, Science Operations, 4002 Basel, Switzerland c Novartis Institutes for BioMedical Research, Neuroscience, 4002 Basel, Switzerland d Novartis Institutes for BioMedical Research, Center for Proteomic Chemistry, 4002 Basel, Switzerland e Department of Chemistry and Biochemistry, University of Berne, 3000 Berne, Switzerland article info Article history: Received 9 February 2011 Revised 28 March 2011 Accepted 3 April 2011 Available online 8 April 2011 Keywords: AMPA receptor antagonists Anticonvulsants Excitatory amino acids Glutamate receptors Quinazoline-2,4-dione sulfonamides abstract Quinazoline-2,4-diones with a sulfonamide group attached to the N(3) ring atom constitute a novel class of competitive AMPA receptor antagonists. One of the synthesized compounds, 28, shows nanomolar receptor affinity, whereas other examples of the series display oral anticonvulsant activity in animal models. Ó 2011 Elsevier Ltd. All rights reserved. The ionotropic glutamate receptors (iGluRs) are a family of ion channels that are divided into the three subtypes N-methyl-D-aspar- tate (NMDA), (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazol- yl)propionic acid (AMPA), and kainate receptors. The channels are permeable for Na + ,K + and Ca 2+ and mediate excitatory synaptic transmission. Over-stimulation of these receptors causes an uncon- trolled Ca 2+ -influx into the cells resulting in excitotoxicity and pos- sible cell death. Several disorders are—at least in part—linked to over-activity of iGluRs, such as epilepsy, chronic pain or neuropa- thology ensuing from cerebral ischemia or cardiac arrest. 1 Different types of antagonists acting at various sites of these receptors were shown to have anticonvulsant, neuroprotective or antinociceptive effects in a range of animal models. Therefore, iGluRs are considered as interesting drug targets, and in particular AMPA receptors may offer the opportunity for therapeutic intervention 2 without the side effects associated with inhibition of NMDA receptors. 3 AMPA receptors are composed of four different subunits, GluA1-4, which likely assemble to functional tetrameric hetero- mers. 4 Each subunit consists of three membrane spanning segments, a reentrant loop, an intracellular carboxy terminal domain and an extracellular glutamate binding domain. Since many of the diseases assumed to be related to defects of AMPA receptors are chronic, oral activity will be an important advantage for a drug blocking AMPA receptors. In this Letter we present a novel series of competitive AMPA receptor antagonists of which several examples show oral activity in animal models for anticonvulsant activity. Since the early 1990s a number of heterocyclic compounds have been known to be competitive AMPA receptor antagonists, bearing, as a common structural feature, an acidic group attached to a het- erocyclic ring system. Examples are the broadband antagonist kynurenic acid(I) 5 , 3-oxo-3,4-dihydro-quinoxaline-2-carboxylic acid(II) 6 , or the potent and selective quinoxalinediones CNQX(III), YM90K(IV) 7 and AMP397(V). 8 At physiological pH, quinoxalinedi- ones are deprotonated with the negative charge located on the oxygen atom 9 (VIb). In search for novel scaffolds endorsing AMPA receptor antago- nism, we designed cyclic hydroxamic acids(VII) with a hydroxyl group in position 3, that is, similar to the position of the negatively charged oxygen atom of (VIb). The N–OH functionality of (VII) has apK a value of 7–7.5, consistent with a partial deprotonation at physiological pH. Several compounds of type VII with various sub- stituents on the benzene ring were prepared and some were found to be competitive antagonists at AMPA receptors. 10 However, the compounds were not active after oral administration in animal models testing for anticonvulsant effects; at best, activity after intraperitoneal administration was found. In general, these 0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2011.04.017 ⇑ Corresponding author. Tel.: +41 61 324 66 08; fax: +41 61 696 24 55. E-mail address: manuel.koller@novartis.com (M. Koller). Bioorganic & Medicinal Chemistry Letters 21 (2011) 3358–3361 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl