Supporting Information. Discovery of. 2-(2-Oxo-1-Phenyl-5-Pyridin-2-yl-1,2-Dihydropyridin-3-yl)Benzonitrile. (Perampanel): A Novel, Noncompetitive

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1 Supporting Information Discovery of 2-(2-Oxo-1-Phenyl-5-Pyridin-2-yl-1,2-Dihydropyridin-3-yl)Benzonitrile (Perampanel): A Novel, Noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic Acid (AMPA) Receptor Antagonist Shigeki Hibi *, Koshi Ueno, Satoshi Nagato, Koki Kawano, Koichi Ito, Yoshihiko Norimine, Osamu Takenaka, Takahisa Hanada, and Masahiro Yonaga Medicinal Chemistry, Biopharmacology, and Drug Metabolism and Pharmacokinetics, Tsukuba Research Laboratories, Eisai Co., Ltd, Tokodai, Tsukuba-shi, Ibaraki , Japan Contents: Table s1. HPLC Purity Data for Biologically Tested Compounds Table s2. Inhibition of Ligand Binding to 63 Targets by Compound 6 S1

2 Table s1. HPLC Purity Data for Biologically Tested Compounds Retention % Compound Formula (Calcd) time, t R Purity No. (M) (Found) [M+H]+ (min) (254 nm) 6 C 23 H 15 N 3 O >99 8a C 15 H 12 N 2 O >99 8b C 16 H 14 N 2 O >99 8c C 15 H 18 N 2 O >99 8d C 15 H 18 N 2 O >99 8e C 12 H 14 N 2 O >99 8f C 16 H 14 N 2 O C 16 H 14 N 2 O C 17 H 13 NO >99 16 C 17 H 13 NO >99 17 C 23 H 17 NO >99 24a C 22 H 16 N 2 O >99 24b C 23 H 15 N 3 O c C 23 H 15 N 3 O >99 24d C 22 H 15 FN 2 O >99 24e C 22 H 15 ClN 2 O f C 23 H 18 N 2 O >99 24g C 23 H 18 N 2 O h C 21 H 14 FN 3 O >99 24i C 21 H 14 ClN 3 O >99 24j C 22 H 14 N 4 O >99 28a C 21 H 15 N 3 O >99 28b C 22 H 14 N 4 O c C 19 H 13 N 3 OS d C 21 H 14 ClN 3 O e C 20 H 12 N 4 OS >99 28f C 22 H 14 F 3 N 3 O >99 28g C 20 H 13 FN 4 O >99 33a C 23 H 15 N 3 O b C 23 H 15 N 3 O S2

3 Retention % Compound Formula (Calcd) time, t R Purity No. (M) (Found) [M+H]+ (min) (254 nm) 33c C 24 H 16 N 2 O >99 33d C 24 H 15 FN 2 O e C 22 H 14 N 2 OS f C 25 H 15 N 3 O >99 33g C 25 H 18 N 2 O >99 33h C 22 H 14 N 2 OS >99 38a C 24 H 17 N 3 O >99 38b C 24 H 17 N 3 O >99 38c C 24 H 17 N 3 O >99 38d C 22 H 13 FN 4 O e C 24 H 14 N 4 O >99 38f C 24 H 14 N 4 O g C 23 H 16 N 4 O >99 The purity of the biological tested compounds was determined by an analytical HPLC method. The parameters of the HPLC method were as follows: Accucore RP-MS column ( mm, 2.6 µm); mobile phase: A = H 2 O with 0.1% HCO 2 H, B = acetonitrile with 0.1% HCO 2 H, 0 1 min, 0% B; 1 4 min, 0% B 100% B; 4 8 min, 100% B; 8 11 min, 0% B; flow rate = 0.4 ml/min; detector: UV 254 nm; run time = 11 min. S3

4 Table s2. Inhibition of Ligand Binding to 63 Targets by Compound 6 % Inhibition Ki (M) by Targets Radioligand Reference Compound Reference Compound 6 Compound (1.25 µm) AMPA [ 3 H]AMPA (+/-)AMPA Br 3.90E Kainate [ 3 H]Kainic acid Kainic acid 1.12E NMDA [ 3 H]CGP NMDA 2.09E NMDA-glycine [3H]MDL-105,519 MDL-105, E Glycine strychnine sensitive [ 3 H]Strychinine Strychinine Nitrate 1.71E GABA A, agonist [ 3 H]GABA GABA 6.78E GABA A, benzodiazepine [ 3 H]Flunitrazepam Clonazepam 1.31E GABA B [ 3 H]CGP 54626A (+/-)Baclofen 1.01E Adenosine, nonselective [ 3 H]NECA NECA 2.90E Adrenergic, α1 [ 3 H]7-MeOxy-Prazosin Phentoramine 2.85E Adrenergic, α2 [ 3 H]RX Phentoramine 2.39E Adrenergic, β [ 3 H]DHA Alprenolol HCl 2.53E Norepinephrine transporter [ 3 H]Nisoxetine Desipramine HCl 1.29E Dopamine transporter [ 3 H]WIN 35,428 GBR E Dopamine, nonselective [ 3 H]Spiperone Spiperone HCl 6.76E Histamine, H1 [ 3 H]Pyrilamine Triplolidine HCl 5.53E Histamine, H2 [ 125 I]Aminopotentidine Tiotidine 7.12E Histamine, H3 [ 3 H]N-α-MeHistamine N-α-MeHistamine 7.91E Melatonin [ 125 I]2-Iodomelatomin 2-Iodomelatomin 7.31E Serotonin, [ 3 H]Citalopram, transporter N-Methyl Imipramine HCl 1.52E Serotonin, Methysergide [ 3 H]LSD nonselective maleate 8.23E S4

5 Muscarinic, M1 [ 3 H]Scoporamine, (-)Scoporamine, (human) N-Methyl MeBr 4.91E Muscarinic, M2 [ 3 H]Scoporamine, (-)Scoporamine, (human) N-Methyl MeBr 1.36E Muscarinic, nonselective CNS [ 3 H]QNB Atropine sulfate 3.29E Muscarinic, nonselective, [ 3 H]QNB Atropine sulfate 1.83E peripheral Nicotinic [ 3 H]Epibatidine (+/-)epibatidine 5.77E Opiate, nonselective [ 3 H]Naloxone Naloxone HCl 1.93E Sigma, nonselective [ 3 H]DTG Haloperidol 3.51E Acetylcholinesterase Acetylcholine Eserine 9.68E Choline acetyltransferase [ 14 C]Acetyl Coenzime MNEP 2.08E Glutamic acid AminoOxy acetic [ 14 C]Glutamic acid decarboxylase acid 4.99E MAO-A [ 14 C]5HT Ro HCl 6061E MAO-B [ 14 C]Phenylethylamine Ro HCl 1.28E Estrogen [ 125 I]3,17B-Estradiol, 16α 17-B-Estradiol 9.54E Testosterone [ 3 H]Methyltrienolone Methyltrienolone 3.81E Calcium, L [ 3 H]Nitrendipine Nifedipine 2.10E Calcium, N [ 125 I]Conotoxin GVIA ω-conotoxin GVIA 1.21E Potassium, ATP sensitive [ 3 H]Glibenclamide Glibenclamide 3.05E Potassium, Ca 2+ activated, VI [ 125 I]Apamin Apamin 3.98E Potassium, Ca 2+ activated, VS [ 125 I]Charibdotoxin Charybdotoxin 6.10E Sodium, Site 1 [ 3 H]Saxitoxin Tetrodotoxin 9.44E Sodium, Site 2 [ 3 H]Batrachotoxin A 20-α-Benzo Aconitine 8.06E NOS [ 3 H]NOARG NOARG 3.29E Leukotriene B4 [ 3 H]LTB 4 LTB E S5

6 Leukotriene D4 [ 3 H]LTD 4 LTD E Thromboxane A2 [ 3 H]SQ 29,548 Pinane-thromboxane 8.27E Corticotropin Releasing Factor [ 125 I]Tyr0-oCRF Tyr0-oCRF 3.66E Oxytocin [ 3 H]Oxytocin Oxytocin 8.18E Platelet Activating Factor, PAF [ 3 H]Hexadecyl, PAF C16 PAF 4.23E Thyrotropin Releasing Hormone, [ 3 H]-(3MeHis2)TRH (3MeHis2)TRH 9.52E TRH Angiotensin II, AT1 [ 125 I]-(Sar1-Ile8) Angiotensin II Angiotensin II 7.05E Angiotensin II, AT2 [ 125 I]Thr4-Angiotensin II Angiotensin II 3.72E Bradykinin, BK2 [ 3 H]Bradykinin Bradykinin TFA 5.90E Cholecystokinin, CCK1 [ 125 I]CCK-8 CCK-8 (sulfated) 1.79E Cholecystokinin, CCK2 [ 125 I]CCK-8 CCK-8 (sulfated) 1.19E Endothelin, ET-A [ 125 I]Endothelin-1 Endothelin E Endothelin, ET-B [ 125 I]Endothelin-1 Endothelin E Galanin [ 125 I]Galanin Galanin (Porcine) 4.21E Neurokinin, NK1 [ 3 H]Substance P Substance P 1.33E Neurokinin, NK2 (Human) [ 125 I]NKA Neurokinin A 8.94E Neurokinin, NK3 [ 125 I]Eledoisin Eledoisin 7.21E Vasoactive intestinal peptide [ 125 I]VIP VIP 5.82E Vasopressin 1 [ 3 H]Vasopressin-1 antagonist Arg8-Vasopressin 8.89E Experimental Procedure (performed by NovaScreen): Ligand binding assays were performed in extracts or membrane fractions obtained from various tissues and from cell lines expressing the respective targets. A radioactively labeled ligand specific for each target was added at a concentration approximately equivalent to the ligand's Kd, and compound 6 was added at a concentration of 1.25 µm. In the negative controls no compound 6 as added. In the positive controls, S6

7 ligands with known Kis for each target were added instead of compound 6 (listed as "reference compound" in the table). After incubation for a period of time sufficient to allow equilibrium binding, the ratio of bound and unbound radioactivity was measured. From this ratio the % inhibition of binding by compound 6 was determined. Data are the result of two experiments. The end of paper S7

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