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(12) United States Patent (10) Patent No.: US 9,456,997 B2 Stauffer Et Al

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(12) United States Patent (10) Patent No.: US 9,456,997 B2 Stauffer Et Al USOO9456997B2 (12) United States Patent (10) Patent No.: US 9,456,997 B2 Stauffer et al. (45) Date of Patent: Oct. 4, 2016 (54) SELECTIVE INHIBITION OF (52) U.S. Cl. B1-ADRENERGIC RECEPTORS FOR THE CPC ........... A61K 31/137 (2013.01); A61K 3 1/138 TREATMENT OF PEDIATRC HEART (2013.01); A61K 31/165 (2013.01); A61 K FAILURE 3 1/35 (2013.01); A61K 31/352 (2013.01); (75) Inventors: Brian Stauffer, Aurora, CO (US); A61K 45/06 (2013.01) Carmen Sucharov, Aurora, CO (US); (58) Field of Classification Search Shelley Miyamoto, Aurora, CO (US) CPC ............. A61K 31/137; A61K 31/138: A61 K (73) Assignee: THE REGENTS OF THE 3 1/165; A61K 31/35; A61K 31/352: A61 K UNIVERSITY OF COLORADO, A 45/06 BODY CORPORATE, Denver, CO See application file for complete search history. (US) (56) References Cited (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 U.S. PATENT DOCUMENTS U.S.C. 154(b) by 215 days. 6,545,040 B1 4/2003 Xhonneux et al. 2007/OO 14733 A1 1/2007 O'Donnell et al. (21) Appl. No.: 13/817,969 (Continued) (22) PCT Filed: Aug. 25, 2011 FOREIGN PATENT DOCUMENTS (86). PCT No.: PCT/US2O11AO49123 WO WO2006130174 * 12/2006 ........... A61K 31,352 S 371 (c)(1), WO WO 2009,1384.51 11/2009 (2), (4) Date: Jun. 6, 2013 OTHER PUBLICATIONS (87) PCT Pub. No.: WO2012/027557 Ahmet et al., “Beneficial effects of chronic pharmacological PCT Pub. Date: Mar. 1, 2012 manipulation of beta-adrenoreceptor Subtype signaling in rodent (65) Prior Publication Data dilated ischemic cardiomyopathy'. Circulation, 110: 1083-1090. 2004. US 2013/0296416 A1 Nov. 7, 2013 (Continued) Related U.S. Application Data Primary Examiner — Savitha Rao (60) Provisional application No. 61/377.277, filed on Aug. (74) Attorney, Agent, or Firm — Parker Highlander PLLC 26, 2010. (57) ABSTRACT (51) Int. Cl. A6 IK3I/37 (2006.01) Provided are methods of treating heart failure in children A6 IK3I/38 (2006.01) using B1-selective adrenergic receptor antagonists, alone or A6 IK3I/352 (2006.01) in combination with other agents, including B-2-selective A6 IK 45/06 (2006.01) adrenergic receptor agonists. (Continued) 12 Claims, 12 Drawing Sheets i-fi 2 - i i O O it. 8 6 G 40 s t 2 2t Affilif Fiattic Actii Petric US 9,456.997 B2 Page 2 (51) Int. Cl. Dalla Libera et al., “Skeletal muscle proteins oxidation in chronic A6 IK3I/I65 (2006.01) right heart failure in rats: can different beta-blockers prevent it to the same degree?”, Int. J. Cardiol., 143: 192-199, 2010. A6 IK3I/35 (2006.01) Foerster et al., “Pediatric heart failure therapy with beta-adrenocep tor antagonists'. Pediatric Drugs, 10(2):125-134, 2008. (56) References Cited Harding et al., “Cardiac beta ARK 1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart U.S. PATENT DOCUMENTS failure', Proc. Natl. Acad. Sci. USA, 98:58.09-5814, 2001. 2007, OO14734 A1 1/2007 O'Donnell et al. International Preliminary Report on Patentability issued in Interna 2007/025995.0 A1 11/2007 Sheth et al. tional Application No. PCT/US 11/49123, mailed Mar. 7, 2013. 2009, 0215844 A1 8, 2009 Davis et al. International Preliminary Report and Written Opinion issued in 2009, 0227646 A1 9, 2009 Davis et al. International Application No. PCT/US 11/49123, mailed Jan. 27. 2012. International Preliminary Report and Written Opinion issued in OTHER PUBLICATIONS International Application No. PCT/US 11/48942, mailed Apr. 10, 2012. Ahmet et al., “Cardioprotective and survival benefits of long-term Kilinc et al., “Adrenomedullin and nitrite levels in children with combined therapy with beta2 adrenoreceptor (AR) agonist and dilated cardiomyopathy'. Pediatric Cardiology, 24(4):381-385, betal AR blocker in dilated cardiomyopathy postmyocardial infarc 2003. tion”, JPET, 325:491–499, 2008. Kozlik et al., “Myocardial beta-adrenoreceptor density and the Ahmet et al., “Pharmacological stimulation of beta2-adrenergic distribution of beta-1 and beta-2 adrenoreceptor Subpopulations in receptors (beta2AR) enhances therapeutic effectiveness of betal AR children with congenital heart disease.” Eur J Pediatrics, 150(6): blockade in rodent dilated ischemic cardiomyopathy', Heart Fail 388-94, 1991. ure Rev., 10:289-296, 2005. Kozlik-Feldmann et al., “Distribution of myocardial beta Baker, “The selectivity of 3-adrenoreceptor antagonists at the adrenoreceptor Subtypes and coupling to the adenylate cyclase in human B1, B2 and B3 adrenoreceptors'. British Journal of Phar children with congenital heart disease and implications for treat macology, 144:317-322, 2005. ment”. Clin Pharmacology, 33(7): 588-95, 1993. Bartholomeu et al., “Intracellular mechanisms of specific beta Lowes et al., “Myocardial gene expression in dilated adrenoceptor antagonists involved in improved cardiac function and cardiomyopathy treated with beta-blocking agents'. N. Engl. J. survival in a genetic model of heart failure'. J. Mol. Cell Cardiol. Med., 346:1357-1365, 2002. 45:240-249, 2008. Milting et al., “Selective upregulation of beta1-adrenergic receptors Boknik et al., “Protein phosphatase activity is increased in a rat and dephosphorylation of troponin I in end-stage heart failure model of long-term beta-adrenergic stimulation’. Naunyn. patients supported by ventricular assist devices”. J. Mol. Cell Schmiedebergs Arch. Pharmacol., 362:222-231, 2000. Cardiol., 41.441-450, 2006. Bristow and Feldman, “Changes in the receptor-G protein-adenylyl Moen and Wagstaff, “Nebivolol: A Review of its Use in the cyclase system in heart failure from various types of heart muscle Management of Hypertension and Chronic Heart Failure', Adis disease”. Basic Res. Cardiol. 87(Suppl 1): 15-35, 1992. Drug Evaluation, 6(10); 1359-1409, 2006. Bristow et al., “Beta 1- and beta 2-adrenergic receptor Subpopula Moffett et al., “Future pharmacologic agents for treatment of heart tions in nonfailing and failing human ventricular myocardium: failure in children', Pediatr Cardiol., 27:533-551, 2006. coupling of both receptor types to muscle contraction and selective Shaddy et al., "Carvedilol for Children and Adolescents with Heart beta 1-receptor down-regulation in the heart'. Circulation Research, Failure: A Randomized Controlled Trial”, JAMA, 298(10): 1171 59; 297-309, 1986. 1179, 2007. Brixius et al., “Nebivolol, bucindolol, metoprolol and carvedilol are Whaley-Connell et al., “Nebivolol reduces proteinuria and renal devoid of intrinsic sympathomimetic activity in human myocar NADPH oxidase-generated reactive oxygen species in the trans dium”. British Journal of Pharmacology, 133: 1330-1338, 2001. genic Ren2 rat', Am. J. Nephrol. 30:354-360, 2009. Cheng, “Nebivolol: A Third-Generation B-Blocker for Hyperten sion'. Clinical Therapeutics, 31(3): 447-462, 2009. * cited by examiner U.S. Patent Oct. 4, 2016 Sheet 1 of 12 US 9,456,997 B2 s s s fugao it filliotii) iOSSaida if-i jetti U.S. Patent Oct. 4, 2016 Sheet 2 of 12 US 9,456,997 B2 S8 82ifetiii tioissatire fiti ateja to & ice r lo Y S8 82 litti iSS3itixa iii. 3.83 U.S. Patent Oct. 4, 2016 Sheet 3 of 12 US 9,456,997 B2 pk0.01 p<0.0001 p&t.0005 4.86 C t S C F. U.S. Patent Sheet 4 of 12 US 9,456,997 B2 isie (; 32.Éitti itjSSaita tigatid 3,883 U.S. Patent Oct. 4, 2016 Sheet S of 12 US 9,456,997 B2 s 5. & s S s is co - ca is r is s (Y, \ y iii-x8 is p32.eiitii toissaicise tigatid 3.8pay S 4. s U.S. Patent Oct. 4, 2016 Sheet 6 of 12 US 9,456,997 B2 iii. alytic fillyHC 2 8 1.6 1.4 1.2 1 - 8 6 4. 2 175 i 5 ONon-failing 12.5 M Failing 2. 18 i.3 U.S. Patent Oct. 4, 2016 Sheet 7 of 12 US 9,456,997 B2 Aiii alytic (Alyht pk0,005 i8 - U.S. Patent Oct. 4, 2016 Sheet 8 of 12 US 9,456,997 B2 s &N pHd - OLS #######3 ified 6S 6; AS He 9S 6 - 7:S y 8 iOS U.S. Patent Oct. 4, 2016 Sheet 9 of 12 US 9,456,997 B2 Mouse Study design. Young and Older Mice isoproterenol Vehicle (AA) BeiaiiOCker U.S. Patent Oct. 4, 2016 Sheet 10 of 12 US 9,456,997 B2 (iiifiti figli iii. U.S. Patent US 9,456,997 B2 (iiifiti gift, (iiiffiti fi U.S. Patent Oct. 4, 2016 Sheet 12 of 12 US 9,456,997 B2 £3.sedse: (Y li c\} is r §§ cy afiei Fiji Y to co e s \ s re. tra re CS (S (S 3itieff US 9,456,997 B2 1. 2 SELECTIVE INHIBITION OF The pediatric Subject may be less than 15 years of age, less B1-ADRENERGIC RECEPTORS FOR THE than 12 years of age, less than 10 years of age, or less than TREATMENT OF PEDIATRC HEART 8 years of age. The B1-adrenergic receptor-selective antago FAILURE nist may be at least twice as B1-selective as Metoprolol, three times as B1-selective as Metoprolol, five times as The present application is a national phase application B1-selective as Metoprolol, or 10 times as B1-selective as under 35 U.S.C. S371 of International Application No. Metoprolol. The pediatric subject may suffer from systemic PCT/US2011/049123, filed Aug. 25, 2011, which claims ventricular failure. Ventricular failure could result from benefit of priority to U.S. Provisional Application Ser. No. dilated cardiomyopathy due to idiopathic, post-viral, includ 61/377.277, filed Aug. 26, 2010, the entire content of each 10 ing coxsackie virus, parvovirus, enterovirus, influenza, or of the above-referenced disclosures is specifically incorpo echovirus, familial or genetic causes, such as Fabrys disease, rated herein by reference.
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