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(12) Patent Application Publication (10) Pub. No.: US 2013/0171145 A1 Devi Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2013/0171145 A1 Devi Et Al US 2013 0171145A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0171145 A1 Devi et al. (43) Pub. Date: Jul. 4, 2013 (54) METHODS OF TREATING LIVER DISEASE Publication Classification (75) Inventors: Lakshi A. Devi, New Rochelle, NY (51) Ek'.I/7076 (2006.01) y Raphael Rozenfeld, Swampscott, C07K 6/28 (2006.01) A613 L/454 (2006.01) (52) U.S. Cl. (73) Assignee: MOUNTSINAISCHOOL OF CPC ........... A6 IK3I/7076 (2013.01); A61 K3I/454 MEDICINE, New York, NY (US) (2013.01); C07K 16/2869 (2013.01); C07K I6/286 (2013.01) (21) Appl. No.: 13/575,220 USPC ....... 424/136.1: 514/326; 514/45; 530/387.3: 435/7.1 (22) PCT Filed: Jan. 25, 2011 (57) ABSTRACT (86). PCT No.: PCT/US2O11?0224.52 Compounds and compositions useful for the treatment of S371 (c)(1), liver diseases and methods of treating liver diseases are dis (2), (4) Date: Mar. 18, 2013 closed. The compounds of the invention specifically interact with heteromers of cannabinoid receptors as compared to O O monomers or homodimers. The invention also relates to Related U.S. Application Data methods of screening for compounds useful for the treatment (60) Provisional application No. 61/297.895, filed on Jan. of liver diseases and to methods of screening for diacylglyc 25, 2010. erol lipase inhibitors. Patent Application Publication Jul. 4, 2013 Sheet 1 of 21 US 2013/0171145 A1 CassX, FIG. 1D (88xis Patent Application Publication Jul. 4, 2013 Sheet 2 of 21 US 2013/0171145 A1 CBR AT1R A2aR PDGFRB P:A2aR Calnexin FIG. 1G FIG. 1H Patent Application Publication Jul. 4, 2013 Sheet 3 of 21 US 2013/0171145 A1 xss S & R S. &S FIG . 2A &---&sssssss ? ×* ? ? „zzzzzzzzzzzzzzzz ? FIG. 2B FIG. 2C Patent Application Publication Jul. 4, 2013 Sheet 4 of 21 US 2013/0171145 A1 HEK/AT1R HEK/CB1R/AT1R Angll Angll SR THL SR THL c) O O 9X 80 s E 7060 SS s & 40 30 2010 O O Šs 200 cS s c S c S O S 3 150 s s C S CC s s 100 Na s Y s U S N14. 50 L S O s BaSal Control CB1R SR Hu210 SiRNA FIG. 3B Angll Patent Application Publication Jul. 4, 2013 Sheet 5 of 21 US 2013/0171145 A1 Angll Basal Angll THL THL Hu210 HEio 3 175s s $ 8. 150 Sb 125 s CCE 100 s 75 nz 50 25 & LO Os SSSSSSSSSSSSSSSSSSSSSe &8S Basal Angll THL THL Hu210 HU210 FIG. 3C Angll Angll + THL 2AG(M) 0 1e-10 1e-9 1e-8 1e-7 3e-7 1e-6 pERK ERK 125s S. S. 100 S: S$ 758 C S. LLif CMO8 50a. N2 SP s s S. s: s Cl 25 is: a ser Os -10 2AGLogM) FIG. 3D Patent Application Publication Jul. 4, 2013 Sheet 6 of 21 US 2013/0171145 A1 sS. <!--<-<- LOO FIG. 3E Patent Application Publication Jul. 4, 2013 Sheet 7 of 21 US 2013/0171145 A1 {(~~~~ xxxx S. Sass&Sass FIG. 4B xxxxxss&s xxx FIG. 4C Patent Application Publication Jul. 4, 2013 Sheet 8 of 21 US 2013/0171145 A1 S s 50 - Log 2AG) (M) FIG. 5 Patent Application Publication Jul. 4, 2013 Sheet 9 of 21 US 2013/0171145 A1 FIG. 6 CTL Angll THL+Angll FIG. 7 Patent Application Publication Jul. 4, 2013 Sheet 10 of 21 US 2013/0171145 A1 Riysics &: Xysicia & sw A-8s &S: poy is a 8x Patent Application Publication Jul. 4, 2013 Sheet 12 of 21 US 2013/0171145 A1 MAP kinase 0. 0. - 0. (5 S 0. as 0.5 -C 0.4 0. 0. 0.1 0. N \ \ 8.S. & N N &N N &g: Wynss ss & &S S &S &S S &S &S S QSs sisco cois osco o Patent Application Publication Jul. 4, 2013 Sheet 14 of 21 US 2013/0171145 A1 Flag AT1R - (kDa) P:CB1R B: Flag Patent Application Publication Jul. 4, 2013 Sheet 15 of 21 US 2013/0171145 A1 s st D xxx CN s: s S& cg O CN v O V w y D Y O re-emper-per- 8. CNy d did s: . O. O. O. O. O. O. O. O. O. 92 O Co oO OO. OOO. NO. O.Co O.LO W C CN So 5 as 3 N 6 (5 SF 5 (N - O (esuodsel eulxeu 94) Xyyid (esuodsel eulxeu%) Xled/Xled CY) O i. i. i. i Patent Application Publication Jul. 4, 2013 Sheet 16 of 21 US 2013/0171145 A1 s Sc S. Sc O CN v- v (190IS UN peue)00 eSUOdse) Ieu!Xeu%) y1/yd Patent Application Publication Jul. 4, 2013 Sheet 17 of 21 US 2013/0171145 A1 s O cod d d d Cd (eSUOdse. Xeu c cN -09|| -001 (eSUOdsel Xeu%)) yid (uuriI)91||7HS 0 bol'?H Patent Application Publication Jul. 4, 2013 Sheet 18 of 21 US 2013/0171145 A1 COntrol (Angll)(M) 0 pERK 175 s- 150 S S COntrol 125 s 8 DNGod 100 xS. 7 5 O S -11 -10 -9 -8 Log Angll (M) xxxxYxxxxxxxxyyxxxxxxxxxxxxxxxxxxxxxxssxxxxxxxxxxYxxxxYxxxxYxxxxYxxxxYs -10 -9 -9 Log Angll (M) FIG. 11A Patent Application Publication Jul. 4, 2013 Sheet 19 of 21 US 2013/0171145 A1 Control PTX Angll)pERK (M) 0 1e-11 1e-10 1e-9 3e-9 1e-8 0 1e-11 1e-10 1e-9 3e-9 1e-8 ERK 2 110x100 COntrol S. 90 & PTX 3 80 is 70 E 60 S 50 40 Na 30 G 20 C 10.O Wyms.S.x^* -11 -10 -9 -8 Log Angll (M) S CB1R SCB1R+PTX -11 -10 9 8 Log Angll (M) FIG. 11B Patent Application Publication Jul. 4, 2013 Sheet 20 of 21 US 2013/0171145 A1 —Control - — (AngllpERK (M) 0.1e-111e-10.1e-93e-91e-8 0.1e-111e-10.1e-93e-9 1e-8 ERK 110 2 100. S Control Og 8090 FSK is 70 60 S. 50 £ 40 30 & 20 10 O-11 & -10 -9 -8 FIG. 11C Log Angll (M) COntrol Si Barrestin2 & Control & si?.Arr2 O $ssssssssssssssssssssssssssssssssssssssssssssssssss -11 - 10 -9 -8 LOg Angll (M) FIG. 1 1D Patent Application Publication Jul. 4, 2013 Sheet 21 of 21 US 2013/0171145 A1 Wrr Š $ S S : & S: S S ; : S Š 8 S & & & S S S & S 8 r R US 2013/0171145 A1 Jul. 4, 2013 METHODS OF TREATING LIVER DISEASE Myers Squibb also discontinued development of its CBR antagonist Otenabant (CP-945,598) following the problems GOVERNMENT SPONSORED RESEARCHOR seen during clinical use of the similar drug Rimonabant. DEVELOPMENT Therefore, what are needed are specific antagonists that do 0001. This invention was made with support received from not have these systemic, toxic side effects. the National Institutes of Health, Department of Health and 0005 N-arachidonoyl-ethanolamine (AEA, anandamide) Human Services, under grant no. DAO8863. The U.S. gov and 2-arachidonoyl glycerol (2-AG) are the two most studied endocannabinoids. They are biosynthesized by cleavage of ernment has certain rights in the invention. their membrane lipid precursors N-arachidonoyl-phosphati FIELD OF THE INVENTION dylethanolamine and Sn-1-acyl-2-arachidonoylglycerols (DAGs) respectively, and then inactivated by intracellular 0002 The present invention is related to compounds and hydrolyzing enzymes. The biological activity of AEA and compositions useful for the treatment of liver diseases and 2-AG is mainly mediated by activation of the cannabinoid related Screening and therapeutic methods. The present receptors CBR and CBR. invention also relates to methods of screening for diacylglyc 0006 2-AG has a variety of effects in vivo; it is a mediator erol lipase inhibitors. of neurite outgrowth, during brain development, or as retro grade signal mediating depolarization-induced Suppression BACKGROUND OF THE INVENTION of neurotransmission and synaptic plasticity, in the adult 0003. A fundamental question in liver biology is how type brain. It protects neurons from inflammation by preventing I cannabinoid receptors (CBRs) mediate liver fibrosis. Can Cox2 gene expression (D2). In addition, 2-AG is involved in nabinoid receptors are a class of G-protein coupled receptors metabolic regulation and diseases. For example, it is involved (GPCRs). Cannabinoid receptors exhibit marginal expression in bone formation (D3), in obesity (its concentration is in the normal liver but undergo enhanced expression in the increased in several tissues and in the circulation of obese fibrotic human liver, predominately in activated hepatic stel persons (D4)). 2-AG is highly upregulated during chronic late cells (HSCs). A critical aspect in chronic liver disease is liver diseases and is implicated in the pathogenesis of non the activation of resident HSCs into proliferative, contractile, alcoholic fatty liver disease, progression of fibrosis to cirrho and fibrogenic cells. These myofibroblasts produce an excess sis and the development of the cardiovascular abnormalities of extracellular matrix proteins including collagens, resulting of cirrhosis, such as the hyperdynamic circulatory syndrome in fibrosis. In these cells, specific mitogenic signaling cas and cirrhotic cardiomiopathy (D5). cades, upon activation of naturally occurring GPCRS Such as 0007 2-AG is produced from the hydrolysis of phosphoi AT1R and adenosine 2A receptor (A2aR) contribute to the nositol bisphosphate (PIP2), catalyzed by the PIP2-selective fibrosis. HSCs are the cells primarily responsible for the phospholipase C, or from the hydrolysis of phosphatidic acid fibrogenic response in the liver'. Preventing the expression or (PA), catalyzed by a PA phosphohydrolase into diacylglycer activation of CBRs attenuates the development of fibrosis. ols (DAGs). DAGs are then converted into 2-AG by sn-1 CBRS contribute to fibrogenic response, since administra selective-DAG lipases (DAGLs). Two sn-1 DAG lipase tion of the CBR antagonist Rimonabant (SR141716) or isozymes (DAGLC, and DAGL(3) have been cloned and enzy geneticablation of CBR inhibits fibrosis progression in three matically characterized (D6).
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