Optimization of a Novel Quinazolinone-Based Series of Transient Receptor Potential A1 (TRPA1) Antagonists Demonstrating Potent In Vivo Activity

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1 Supporting Information Optimization of a Novel Quinazolinone-Based Series of Transient Receptor Potential A1 (TRPA1) Antagonists Demonstrating Potent In Vivo Activity Laurie B. Schenkel, Philip R. Olivieri, Alessandro A. Boezio, Holly L. Deak, Renee Emkey, Russell F. Graceffa, Hakan Gunaydin, Angel Guzman-Perez, Josie H. Lee, Yohannes Teffera, Weiya Wang, Beth D. Youngblood, Violeta L. Yu, Maosheng Zhang, Narender R. Gavva, Sonya G. Lehto, Stephanie Geuns- Meyer Table of Contents TRPA1 Potency Data with Standard Deviations.S2 CEREP Panel Data for Compound 27.S3 Computational Method for Calculating Predicted π-stacking Interaction of Compound 27..S4 Data and Experimental Procedure for 3-((3-(4-chlorophenethyl)-1,2,4-oxadiazol-5-yl)methyl)-2- methylpyrido[2,3-d]pyrimidin-4(3h)-one..s5 Summary of Reported Data for Compound 27..S6 S1

2 Table S1. TRPA1 Potency Data with Standard Deviations Cmpd FLIPR rtrpa1 (µm) FLIPR htrpa1 (µm) Ca 2+ Flux rtrpa1 (µm) Ca 2+ Flux htrpa1 (µm) a a / / Undefined a >8.33 a a Undefined a,b 7 >16.7 > >16.7 > / / Undefined b > >16.7 > / / / / a a a 1.33 a a 1.46 a / / / / / / / / / / / / / / / / / / a a / / / / / / / / / / / / a 2.12 a / / / / / / / / / / / / / / / / / / / / Data represents the mean of 2 independent dose-response curves, except where noted. Data is from a single dose-response curve. b Inhibition crossed the 50% threshold, but a curve could not be fit. S2

3 Table S2. CEREP Panel Data for Compound 27. Inhibition of Radioligand Binding at 10 µm 27. Assay % Inhibition of Control Specific Binding 5-HT2B (h) (antagonist) 23 Ca2+ channel (L, dihydropyridine site) (antagonist) 20 Cl- channel (GABA-gated) (antagonist) 19 CCR2 (h) (agonist) 19 5-HT2A (h) (antagonist) 16 5-HT5a (h) (agonist) 6 5-HT4e (h) (antagonist) 5 adenosine transporter (antagonist) 4 5-HT6 (h) (agonist) 4 H2 (h) (antagonist) 4 D2S (h) (antagonist) 3 A3 (h) (agonist) 3 alpha 2A (h) (antagonist) 1 5-HT1A (h) (agonist) 0 delta 2 (DOP) (h) (agonist) -1 sigma (non-selective) (h) (agonist) -1 beta 1 (h) (agonist) -1 alpha 1A (h) (antagonist) -2 NK1 (h) (agonist) -2 CXCR2 (IL-8B) (h) (agonist) -2 D1 (h) (antagonist) -2 BZD (peripheral) (antagonist) -3 A2A (h) (agonist) -3 kappa (KOP) (agonist) -4 H1 (h) (antagonist) -6 dopamine transporter (h) (antagonist) -6 UT (h) (agonist) -7 5-HT1B (antagonist) -7 beta 2 (h) (agonist) -7 NK2 (h) (agonist) -7 mu (MOP) (h) (agonist) -8 M1 (h) (antagonist) -9 H3 (h) (agonist) -10 MC4 (h) (agonist) -10 Ca2+ channel (L, diltiazem site) (benzothiazepines) (antagonist) -11 CCK1 (CCKA) (h) (agonist) -12 CB1 (h) (agonist) -12 M4 (h) (antagonist) -14 D3 (h) (antagonist) -14 norepinephrine transporter (h) (antagonist) -16 sst4 (h) (agonist radioligand) -20 S3

4 Computational Method for Calculating Predicted π-stacking Interaction of Compound 27 Benzene-imidazole face-to-face interaction energy was computed at the M052X/6-31+G(d) level of theory by using G09 program. The face-to-face geometry was obtained by minimizing the protonated histidine-benzene face-to-face geometry with Cs point group symmetry constraint. The interaction energy between neutral histidine and benzene group was obtained by replacing the protonated histidine with the neutral one in this geometry and calculating the single point interaction energy. Coordinates: 21 imidazole-benzene N C H C H N H C H C H C H C H S4

5 C H C H C H Data and Experimental Procedure for 3-((3-(4-chlorophenethyl)-1,2,4-oxadiazol-5-yl)methyl)-2- methylpyrido[2,3-d]pyrimidin-4(3h)-one rtrpa1 IC 50 htrpa1 IC 50 (µm) a (µm) a RLM/HLM Cl int, app (µl/min/mg) (n=1) (n=1) >399 / clogp 3-((3-(4-chlorophenethyl)-1,2,4-oxadiazol-5-yl)methyl)-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one. The title compound was prepared according to General Procedure D using 2-aminonicotinic acid, (3-(4- chlorophenethyl)-1,2,4-oxadiazol-5-yl)methanamine (48), and trimethyl orthoacetate in place of trimethylorthoformate, and was isolated as a yellow oil in 83% yield. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm (m, 1 H), (m, 1 H), (m, 1 H), (m, 5 H), 5.69 (s, 2 H), (m, 4 H) 2.72 (s, 3 H). MS, m/z [M + H] +. S5

6 Summary of Reported Data for Compound 27 TRPA1 Potency Rat TRPA1 IC 50 (FLIPR, µm): Rat TRPA1 IC 50 ( 45 Ca 2+ Flux, µm): Rat TRPA1 EC 50 ( 45 Ca 2+ Flux, µm): >40 Human TRPA1 IC 50 (FLIPR, µm): Human TRPA1 IC 50 ( 45 Ca 2+ Flux, µm): Human TRPA1 EC 50 ( 45 Ca 2+ Flux, µm): >40 Off-Target Potency Human TRPV1 / TRPV4 IC 50 (µm): >10 / >10 Rat TRPV1 / TRPV3 / TRPM8 IC 50 (µm): >10 / >10 / >10 CYP3A4 / CYP2D6 est. IC 50 (µm): >27 / >27 Mouse Nav µm (% block): 10 In Vitro PK RLM/HLM Cl int, app (µl/min/mg): 41 / <14 Rat Plasma free fraction (F u ): MDCK-VC Avg Papp (10-6 cm/s): 44 MDCK-hMDR1 Efflux ratio: 1.3 Solubility SIF (µm): 248 PBS (µm): N HCl (µm): 305 In Vivo PK IV a Oral b CL CL u Vss AUC T inf C max T max F% Cmax (L/h/k (L/k 1/2 T u / (um-hr) (Cmax (h) u ) (h) 1/2 45 Ca 2+ (h) g) g) (um) IC (2.2) a 0.5 mg/kg, 100% DMSO. b 30 mg/kg, 1% Tween 80/2% HPMC/97% water/methanesulfonic acid ph 2.2. S6

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