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(12) Patent Application Publication (10) Pub. No.: US 2013/0252924 A1 Penninger Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2013/0252924 A1 Penninger Et Al US 20130252924A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0252924 A1 Penninger et al. (43) Pub. Date: Sep. 26, 2013 (54) COMPOUNDS AND METHODS FOR Publication Classification TREATING PAIN (51) Int. C. (75) Inventors: Josef Penninger, Vienna (AT); Graham A63/675 (2006.01) Gregory Neely, Sydney (AU); Shane A613 L/496 (2006.01) McManus, Vienna (AT); Henrik A613 L/50 (2006.01) Nilsson, Vienna (AT) A613 L/435 (2006.01) A613 L/506 (2006.01) (73) Assignee: AKRON MOLECULES GMBH, A 6LX3L/277 (2006.01) Vienna (AT) (52) U.S. C. CPC ............. A6 IK3I/675 (2013.01); A61 K3I/506 (21) Appl. No.: 13/884,920 (2013.01); A61 K3I/277 (2013.01); A61 K 3 1/50 (2013.01); A61K3I/435 (2013.01); (22) PCT Fled: Nov. 11, 2011 A6 IK3I/496 (2013.01) USPC ........ 514/81: 514/252.19; 514/521; 514/247; (86) PCT NO.: 514/352: 514/253.06 S371 (c)(1), (2), (4) Date: May 10, 2013 (57) ABSTRACT (30) Foreign Application Priority Data The present invention relates to new therapies to treat pain and related diseases, as well as pharmaceutical compounds Nov. 11, 2010 (EP) .................................. 1O190922.4 for use in said therapies. Patent Application Publication Sep. 26, 2013 Sheet 1 of 25 US 2013/0252924 A1 Fig. 1 A : B Control painless Avoidance 8. 8 9 40 is 20 LE 3 35' as 3. 3s. 45 Temperature C C Paser re. SR + UAS-DCR2 Transgene 0.150- Control c X pairessp . -- store 1.65 Citroff s 0.050- ty F. , , Aidance Africant Noxious heat (46°C D E .3 Hits: 622 (3%) Geries 580 : 00 it O. s s ... No Phenotype 's Woidance Patent Application Publication Sep. 26, 2013 Sheet 2 of 25 US 2013/0252924 A1 Fig. 2 B C 6C W D xs 46C 100 3. 40 80 i. O. .. 3 so 0.6 3520 3 40 0.4 20 0.2 10 . 5. 8x ca's a c N ss s s s 3. a's stj-Gal4>UAS-GFP f Anti-STJ antibody st in situ a sensia Patent Application Publication Sep. 26, 2013 Sheet 3 of 25 US 2013/0252924 A1 Fig. 3 Futch Sti-GalAZUAS-CD8:GFP Overlay wif X elay UAS-sti-IR2Xelaw painless s 5. ite as: issa is st esses 3. i-, of 3, +f-0.65 s (f-0. s 2. 2. 29, "n E. s . 9 1 2 3 is is F is 3 is is s st s st/def 5, st rescue east s sar as gy, reas: (f-08 -- 28 s tri-e,67 3, , s is: s to . o, . a 3 is is is . is e Patent Application Publication Sep. 26, 2013 Sheet 4 of 25 US 2013/0252924 A1 Fig. 4 A. B Brain DRG 3. the are as Targeted o283 . - Endogenous c281 E. Actin so Hot plate D inflammatory pain 40 2O S 30 3. 15 20 5 s e 10 5. s 5 56 2 3 5 Temperature (C) Days after CFA Patent Application Publication Sep. 26, 2013 Sheet 5 of 25 US 2013/0252924 A1 Fig. 5 CACNA2D3 3p21.1 54.5 S. i Acute (wind up) Chronic SSOSS S55 58518 Patent Application Publication Sep. 26, 2013 Sheet 6 of 25 US 2013/0252924 A1 Fig. 6 A Cortex Hippocampus g Cerebellum Olfactory Bulb 3. Olfactory Thalanus Tubercle B Thalamus S11S2 Somatosensory Cortex s 5 s is g 1.25 s S .so i i S. W WX 8 W X at Ss. Sk S. So 2 is a SSC Patent Application Publication Sep. 26, 2013 Sheet 7 of 25 US 2013/0252924 A1 Fig. 7 ES E. E. B Sensory cross-activation C Sensory cross-activation (heat) (tactile) - 2.0 - 2.0 Š, 1.8 SS, 1.8 c 1.6 1.6 1.4 1.4 1.2 is 1.2 9 Oc1.0 9 1.00.8 2 0.6 2 0.6 30.4. 0.4. T. O.2 0.2 OT WIC AC O WC AC Patent Application Publication Sep. 26, 2013 Sheet 8 of 25 US 2013/0252924 A1 Fig. 8 Screening system Genome-wide screen etc. Nira impaired rociception rociception . incapacitated Aidance is is is is is s Aidate Response (ranked) total incapacitated X 100 (total) as ATP synthesis sts rarieties Feited BP (23) a feat resis possgee comprisation fighterest Terr's st is ret organelles sai is Nutfestirriterrodeting Secretary Functers is knocteries Patent Application Publication Sep. 26, 2013 Sheet 9 of 25 US 2013/0252924 A1 E. i C 9 A eaw-Galest R1 B Nuclei sigAL4>UAS-Lamin: GFP C Nuclei stjgAL4>UAS-Lamin:GFP Projections sigAL4-UAS-CD8:GFP Patent Application Publication Sep. 26, 2013 Sheet 10 of 25 US 2013/0252924 A1 Fig. 1O 440C 46°C 500C 530C : g mean 2.41 rear 9. real i34 rear 12 +. .3 i. i.i.2) +/-, 2 control 3 too' ge 2. e. is is . rear 5. riga. as 38 rear 3 5 ea .5 s f. , is ... c.63 ef. .45 a. st so s g s: s at a 2.88 Exit XLIX 38 88: 3. ; * . to mean 3,47 s a . rea is near 35 B. F. a.28) +f. , 8. (+)-2, s ef. G.16. Ed is es s e st rescue ; : a a . Canton S B pairess st? o 5 t 59, Kerman score Patent Application Publication Sep. 26, 2013 Sheet 11 of 25 US 2013/0252924 A1 Fig. 11 A B C D e Von Frey Open field - Time in center E3 8 Boo 350 s s se 2. s ? o : E s 400 3 25 f l 3. s 2 e E F or M. W. s Days after CFA Tail suspension Rotarod a fick g 200- 9. 3. -4 ge 150 iii:g 5. weri E u 4. 22 E 3 5 in 2 E al 0. has us Patent Application Publication Sep. 26, 2013 Sheet 12 of 25 US 2013/0252924 A1 Fig. 12 A Left 3. Patent Application Publication Sep. 26, 2013 Sheet 13 of 25 US 2013/0252924 A1 Fig. 13 A 0.283 o283 left train right brain left brain right brain t xes s ". aw: . : se &W s retire is ": Patent Application Publication Sep. 26, 2013 Sheet 14 of 25 US 2013/0252924 A1 Fig. 14 Total Brain activity (Heat stimulation) A Peak height B Activation volume C s SSC O C 55°C Temperature Temperature Total Brain activity (tactile stimulation) C Peak height D Activation volume Patent Application Publication Sep. 26, 2013 Sheet 15 of 25 US 2013/0252924 A1 a Ceti Structure and Organees related Litochor dria Stricture aircrgariates in AP synthesis 2. Calcitri Sigrating arrrocesses ZDNAFChromatiri Renocietirig :acist 3 Cecycle as Nervous Systern evelopernt Seleasissic 5. Secretory Functions 2. Signating Pathay Transport Braune resperse Cytomegalovirus-DNA repair; 8 s: Garrete genesis and re C Cemigration; 3. infection; gradat development & leftistic Etting; Y development; 6 immuno-suppression; and proliferation; - Heart diseases; 9- S. Cell Cycle; G Hernate poiesis; 3 Cell adhesion; 6.-- Hypoxic; - infantratory; - Metabolism; 27 Nitochordria; Este centracti; - Nervous system;1. Nerotransmitters; rticleic acid retatais; 2. Organ developresent; E. Ca signating, 7 T-- \m pressings Brain's reward -s pathways; 4 is Al-kai, Adipocyte Biaticard Alzheirer ciferentiation; abitatistress;3 Apoptosis: disease A: 5 Patent Application Publication Sep. 26, 2013 Sheet 16 of 25 US 2013/0252924 A1 E. ig. 16 Patent Application Publication Sep. 26, 2013 Sheet 17 of 25 US 2013/0252924 A1 Fig. 17 A PK3CG 722.3 s loss s E. as 106.6 f W.M. 38 g: ss S8. r & a 5. gi g is is: i: if: B rS57.902 C rS5'902 D Hargreaves .5 s 0.25 5 4 e s . 2 3 ? s -.5 -O.5. As G.A. AA G.A. 3. cos Miss ce E F Capsaicin G BM chimeras H Kinase-dead Hot plate Behavior OWT 6 as KO 45 5 75 2 % a . e - 10 es 15 o 2 SE s g: 10 s s s - - W. KD Patent Application Publication Sep. 26, 2013 Sheet 18 of 25 US 2013/0252924 A1 Fig. 18 5 9re 40 / * \ - a.\ s: mM - - - Y- 45 current Current - 40 .5A 35 s 30 o WT KO S 25 s E. scape high \ sits righ C 20 s No 15 s: 10 NN SSBoy seei. ty 5 3.se t yrish y3: O 3. 3. 3. 33 3, 3.5 SO 3, 3.2 3.3 3.4 3.5 Temperature 1 (T + 1000 (K) C capsaicinuM (c.8, in O.O. O.1 0.5 1.O 5.0 is . s it- as - O. 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