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(12) Patent Application Publication (10) Pub. No.: US 2017/0095465 A1 Elenko Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2017/0095465 A1 Elenko Et Al US 201700.95465A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0095465 A1 Elenko et al. (43) Pub. Date: Apr. 6, 2017 (54) METHODS AND COMPOSITIONS FOR application No. 13/592.480, filed on Aug. 23, 2012, TREATMENT OF DISORDERS now abandoned, which is a continuation of applica AMELORATED BY MUSCARNC tion No. 13/348,057, filed on Jan. 11, 2012, now RECEPTOR ACTIVATION abandoned, which is a continuation of application No. 12/840,980, filed on Jul. 21, 2010, now abandoned. (71) Applicant: PureTech Health LLC, Boston, MA (60) Provisional application No. 61/282,658, filed on Mar. (US) 15, 2010, provisional application No. 61/213,853, (72) Inventors: Eric Elenko, Boston, MA (US); filed on Jul. 22, 2009. Andrew C. Miller, East Walpole, MA (US); Philip E. Murray, III, Publication Classification Somerville, MA (US) (51) Int. Cl. A63L/46 (2006.01) (21) Appl. No.: 15/378,796 A69/48 (2006.01) A6II 3/4439 (2006.01) (22) Filed: Dec. 14, 2016 (52) U.S. Cl. Related U.S. Application Data CPC .......... A61K 31/46 (2013.01); A61K 31/4439 (2013.01); A61K 9/48 (2013.01) (63) Continuation-in-part of application No. 15/161,840, filed on May 23, 2016, now abandoned, which is a (57) ABSTRACT continuation of application No. 14/534,698, filed on Nov. 6, 2014, now abandoned, which is a continu Methods for the treatment of CNS disorders using combi ation of application No. 13/858,985, filed on Apr. 9. nations of muscarinic activators and inhibitors, and medi 2013, now abandoned, which is a continuation of caments comprising muscarinic activators and inhibitors. Patent Application Publication Apr. 6, 2017 Sheet 1 of 2 US 2017/009S465 A1 ,{(8))ERHOOSWLEIHILauoose?aul Patent Application Publication Apr. 6, 2017 Sheet 2 of 2 US 2017/0095465 A1 Apr. 6, 2017 METHODS AND COMPOSITIONS FOR efficacy and severe side effects. There is little to no differ TREATMENT OF DISORDERS ence in efficacy between typical and atypical antipsychotics, AMELIORATED BY MUSCARINC most likely due to the fact that both classes of drugs achieve RECEPTOR ACTIVATION their therapeutic effect through the same pharmacological mechanisms (e.g., acting as dopamine receptor antagonists). FIELD OF INVENTION (Nikam et al. Curr Opin Investig Drugs. 9:37. 2008). Side effects of typical antipsychotics include abnormal move 0001. The present invention relates to: (1) a method of ment (e.g., rigidity) whereas atypicals have different but using a combination of one or more muscarinic agonists and equally significant side effects (e.g., major weight gain, one or more muscarinic antagonists for treatment of diseases cardiovascular effects, etc.). The side effect profile of current that are ameliorated by activation of muscarinic receptors antipsychotics further decreases compliance in a patient (e.g., Schizophrenia and related disorders); and (2) a medi population that is already frequently non-compliant. Thus, cament comprising one or more muscarinic agonists and one there exists a clear need for new therapeutics to treat or more muscarinic antagonists. Schizophrenia and related disorders (e.g., schizoaffective disorder). BACKGROUND OF THE INVENTION 0005 Clozapine is an example of an antipsychotic that 0002 The acetylcholine neurotransmitter system plays a has major side effects, including sialorrhea (hypersalivation) significant role in a variety of central nervous system (CNS) which occurs in up to 54% of patients. (Davydov and Botts, and peripheral functions. Acetylcholine signaling occurs Ann Pharmacother: 34:662. 2000). The exact mechanism of through two different families of receptors: nicotinic recep hypersalivation remains unknown. (Rogers and Shramko. tors and muscarinic receptors. Muscarinic cholinergic recep Pharmacotherapy. 20:109. 2000). Clozapine has a complex tors are G-protein coupled receptors with five different pharmacological profile with appreciable activity at a variety receptor subtypes (M1-M5) (Raedler et al. American Jour of receptors, including dopamine receptors, serotonin recep nal of Psychiatry. 160: 118. 2003), each of which are found tors, adrenergic receptors, muscarinic receptors and possibly in the CNS but have different tissue distributions. Activation others. (Coward. BrJ Psychiatry Suppl. 17:5. 1992). Inves of the muscarinic system through use of muscarinic agonists tigators have tried a variety of pharmacological approaches has been suggested to have the potential to treat several in an attempt to counteract sialorrhea, including botulinum diseases including Alzheimer's disease, Parkinson's disease, toxin (Kahl et al. Nervenarzt. 76:205. 2005) as well as the movement disorders and drug addiction. (US 2005/0085463: antipsychotics amisulpride (Croissant et al. Pharmacopsy Langmead et al. Pharmacology & Experimental Therapeu chiatry. 38:38. 2005) and sulpiride. (Kreinin et al. Isr J tics. 117: 232:2008). Genetic evidence has suggested a direct Psychiatry Relat Sci. 42:61. 2005). Efforts have focused link between the muscarinic system and both alcohol addic mostly on alpha2 adrenergic agonists as well as anti-cho tion (Luo X. Et al. Hum Mol Genet. 14:2421. 2005) and linergic drugs due to clozapine's known interaction with nicotine addiction (Mobascher A et al. Am J Med Genet B these receptors. Anti-muscarinic drugs such as pirenzepine Neuropsychiatr Genet. 5:684. 2010). M1 and M4 subtypes have shown efficacy in small scale trials (Schneider et al. have been of particular interest as therapeutic targets for Pharmacopsychiatry. 37:43. 2004), but other trials with the various diseases. For instance, the mood stabilizers lithium same agent found no effect. (Liu et at. J. Clin Psychophar and Valproic acid, which are used to treat bipolar depression, macol. 21.608. 2001). Alpha2 adrenergic agonist such as may exert their effects via the muscarinic system particularly clonidine (Singh et al., J Psychopharmacol. 19:426. 2005) through the M4 subtype receptor. (Bymaster & Felder. Mol have also shown efficacy in reducing sialorrhea in small Psychiatry: 7 Suppl 1:S57. 2002). scale trials. However, Syed et al. reported in a 2008 review 0003. Some of the strongest linkages to the muscarinic that there is inadequate data to guide clinical practice. (Syed system have been with schizophrenia, which is a serious et al. Cochrane Database Syst Rev. 16:3. 2008). mental illness affecting approximately 0.5-1% of the popu 0006) Another approach to the treatment of schizophrenia lation. (Arehart-Treichel. Psych News. 40:9. 2005). The has been use of muscarinic agonists. Muscarinic receptors disease is characterized by a set of symptoms that are are G-protein linked receptors that bind the neurotransmitter generally divided into three categories: 1) Positive symp acetylcholine. (Eglen R M. Auton Autacoid Pharmacol 26: toms (e.g., hallucinations, delusional thoughts, etc.); 2) 219. 2006). To date, five subtypes of muscarinic receptor Negative symptoms (e.g., social isolation, anhedonia, etc.); have been identified and are generally labeled M1, M2, M3, and 3) Cognitive symptoms (e.g., inability to process infor M4, and M5, respectively. (Caulfield MP et al. Pharmacol. mation, poor working memory, etc.). (Schultz. Am Fam Rev. 50: 279. 1998). These muscarinic subtypes vary in Physician. 75:1821. 2007). Patients who suffer from schizo terms of the affinity of various agonists and antagonists for phrenia both experience a major decline in quality of life and the receptors. A number of lines of evidence have suggested are at increased risk for mortality due to a number of factors, that the muscarinic system plays a significant role in the such as an increased suicide rate. (Brown et al. British pathology of schizophrenia. In particular, decreased expres Journal of Psychiatry. 177: 212. 2000). The cost of schizo sion of M1 and M4 receptor subtypes has been noted in phrenia to society is also significant as sufferers of schizo post-mortem studies in deceased schizophrenic patients. phrenia are much more likely to be incarcerated, homeless (Dean et al. Mol Psych. 1: 54. 1996). Likewise, SPECT or unemployed. imaging studies have shown decreased muscarinic availabil 0004 Today, antipsychotics are the mainstay of treatment ity in schizophrenia. (Raedler et al. Am J Psych. 160:118. for schizophrenia. The first generation of antipsychotics are 2003). generally known as “typical antipsychotics” while newer 0007. There is also pharmacological evidence implicat antipsychotics are generally called "atypical antipsychot ing activation of muscarinic receptors as a potential thera ics.” Both typical and atypical antipsychotics have limited peutic approach to schizophrenia. For example, the musca US 2017/00954.65 A1 Apr. 6, 2017 rinic antagonist Scopolamine, which is used to treat motion side effects associated with the agents binding certain sickness, produces cognitive impairment and delusions of muscarinic receptor Subtypes. A need exists for a method of the type seen in Schizophrenia. (Ellis et al. Int. J. Neurop using muscarinic agonists and for a medicament employing sychopharmacol. 9:175. 2006). More selective M1 agonists Such muscarinic agonists that would allow for the therapeu have been Suggested to potentiate glutamate signaling which tic effects associated with activation of muscarinic receptors, could help exert a therapeutic effect. (Jones et al. J. Neuro but with fewer side effects. sci. 28:10422. 2008). In a double-blind placebo controlled trial of Schizophrenic patients using Xanomeline, which has SUMMARY OF THE INVENTION preferential activity at the M1 and M4
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