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(12) United States Patent (10) Patent No.: US 8.481,485 B2 Dimarchi Et Al

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(12) United States Patent (10) Patent No.: US 8.481,485 B2 Dimarchi Et Al USOO8481485B2 (12) United States Patent (10) Patent No.: US 8.481,485 B2 DiMarchi et al. (45) Date of Patent: Jul. 9, 2013 (54) INSULIN ANALOGS 6,630,348 B1 10/2003 Lee et al. 6,746,853 B1 6/2004 Dahiyat et al. 7,045,337 B2 5, 2006 Schultz et al. (75) Inventors: Richard D. DiMarchi, Carmel, IN (US); 7,326,688 B2 2/2008 O'Harte et al. Jie Han, Bloomington, IN (US) 7,521,422 B2 4/2009 Bernard 2002fOO38026 A1 3/2002 Rao et al. (73) Assignee: Indiana University Research and 2002fO160938 A1 10/2002 Brandenburg et al. Technology Corporation, Indianapolis, 2003/O195147 A1 10/2003 Pillutila et al. 2003/0204063 A1 10/2003 Gravel et al. IN (US) 2004.0054130 A1 3/2004 Ng et al. 2004/O121940 A1 6/2004 De Groot et al. (*) Notice: Subject to any disclaimer, the term of this 2005, OO14679 A1 1/2005 Beals et al. patent is extended or adjusted under 35 2005/O1871.47 A1 8, 2005 Newman et al. U.S.C. 154(b) by 0 days. 2006/0171920 A1 8, 2006 Shechter et al. 2006/0210534 A1 9, 2006 Lee et al. 2006/0223753 A1 10/2006 Glass (21) Appl. No.: 13/130,976 2007/0173452 A1 7/2007 DiMarchi et al. 2007/0224119 A1 9, 2007 McTavish (22) PCT Filed: Dec. 18, 2009 2008.0113411 A1 5, 2008 Sheffer 2008.0113905 A1 5/2008 DiMarchi et al. (86). PCT No.: PCT/US2009/068712 2008/O125574 A1 5/2008 Sheffer et al. 2009.0054305 A1 2/2009 Schlein et al. S371 (c)(1), 2009,0176964 A1 7/2009 Walensky et al. (2), (4) Date: May 24, 2011 2009,0192072 A1 7, 2009 Pluta et al. 2011/0065633 A1 3/2011 Dimarchi et al. (87) PCT Pub. No.: WO2010/080606 2011/0288003 A1 11/2011 Dimarchi et al. PCT Pub. Date: Jul. 15, 2010 FOREIGN PATENT DOCUMENTS EP O220958 5, 1987 (65) Prior Publication Data EP 1161452 2, 2000 EP 203.6539 A1 3, 2009 US 2011 FO257091A1 Oct. 20, 2011 EP 2036923 A1 3, 2009 WO 90,12814 11, 1990 WO 93,03174 2, 1993 Related U.S. Application Data WO 1998, 11126 3, 1998 WO 99.46283 9, 1999 (60) Provisional application No. 61/139,221, filed on Dec. WO O2,101.95 2, 2002 19, 2008. WO 2004/067548 8, 2004 WO 2004/O78777 9, 2004 (51) Int. Cl. WO 2005/054291 6, 2005 A6 IK38/28 (2006.01) (Continued) A6 IK38/00 (2006.01) OTHER PUBLICATIONS A6 IK38/04 (2006.01) A6IP5/50 (2006.01) Coy et al., Journal of Medicinal Chemistry, 1973, vol. 16, No. 7. A6IP3/08 (2006.01) 827-829* Yang et al., World J Gastroentero, 2000; 6(3):371-373.* A6IP3/10 (2006.01) Hinds et al., Advanced Drug Delivery Reviews 2002, (54) 505-530.* A6IP 7/2 (2006.01) De, et al., “Investigation of the feasibility of an amide-based prodrug C07K5/00 (2006.01) under physiological conditions.” Int. J. Pept. Res. Ther. 14, pp. C07K 700 (2006.01) 255-262 (2008). C07K 16/00 (2006.01) Madsen, et al., “Structure-activity and protraction relationship of C07K 17/00 (2006.01) long-acting glucagon-like peptide-1 derivatives: Importance of fatty acid length, polarity, and bulkiness,” J. Med. Chem. 50, pp. 6126 (52) U.S. Cl. 6132 (2007). USPC ............... 514/6.2: 514/6.3: 514/6.7: 514/6.8; Mayer et al. Insulin Structure and Function. PeptideScience 2007. 514/6.9; 530/330 88(5):687-713; 688, Fig 1. (58) Field of Classification Search Wang et al. Identification of Site(s) of Insulin Nitration by None Peroxynitrite and Characterization of Its Structural Change. Protein See application file for complete search history. & Peptide Letters 2008, 15: 1063-1067: Abstract, p. 1066, col. 2. (Continued) (56) References Cited Primary Examiner — Marcela M Cordero Garcia U.S. PATENT DOCUMENTS Assistant Examiner — Kaipeen Yang 3,740,385 A 6, 1973 Ondetti (74) Attorney, Agent, or Firm — Barnes & Thornburg LLP 4,275,152 A 6, 1981 Esders et al. 4,741,897 A 5, 1988 Andrews et al. 4,876,242 A 10/1989 Applebaum et al. (57) ABSTRACT 4,985.407 A 1/1991 Foxton et al. Full potency analogs of insulin are provided wherein the 5,359,030 A 10, 1994 Ekwuribe 5,514,646 A 5, 1996 Chance et al. analog comprises a modification of the tyrosine residue at 6,180,767 B1 1/2001 Wickstrom et al. position 19 of the A chain. 6, 197,926 B1* 3/2001 Gaur et al. .................... 530/303 6,476.290 B1 1 1/2002 Wright et al. 22 Claims, 3 Drawing Sheets US 8,481,485 B2 Page 2 FOREIGN PATENT DOCUMENTS Vascular Endothelial Growth Factor and Model Peptides'. AAPS WO 2006/047214 5, 2006 Pharmsci 2000 2(1) article 5: 1-6 (Mar. 17, 2000). WO 2008/021560 2, 2008 Hamel et al “Cyclosporin a prodrugs: Design, synthesis and bio WO 2008/O25528 3, 2008 physical properties”. J. Peptide Research, vol. 63 No. 2 pp. 147-154 WO WO2009034118 A1 3, 2009 (Feb. 2004). WO WO2009034119 A1 3, 2009 Han et al., “IGF-based Insulin Analogs with an A-Chain Lactam.” WO 2009/06.7636 5, 2009 APS poster presentation, 2011. WO 2009.095479 8, 2009 WO WO, 2009/O99763 8, 2009 Han et al., “Insulin Chemical Synthesis. Using a Two-Step Orthogo WO 2010/011313 1, 2010 nal Formation of the Disulfides.” APS poster presentation. WO 2010/071807 6, 2010 Han et al., “Structure-Activity Relationship of Insulin at Position WO 2010/080605 T 2010 A'.” APS poster presentation. WO 2011, 163012 12/2011 Harris, J. Milton, Final Word: PEGylation—A "Sunset'Technology? <http://licence.icopyright.net/user/viewFreeUse. OTHER PUBLICATIONS act?fuid=OTU1NT3OA%3D%3D>, BioPharm International, Jun. Schilling et al. Degradation of Insulin by Trypsin and Alpha 1, 2004. Chymotrypsin. Pharmaceutical Research 1991, 8(6):721-727; Hua et al., “Design of an active ultrastable single-chain insulin ana Abstract, p. 727, col. 1. log.” J. of Biological Chemistry, Mar. 2008, vol. 283, No. 21, 14703 Kristensen et al. Alanine Scanning Mutagenesis of Insulin. The Jour 14716. nal of Biological Chemistry 1997, 272(20): 12978-12983; p. 12982, Joost, H.G., et al., Quantitative Dissociation of Glucose-Transport col. 1, first full para, p. 12982, col. 1, second full para. Stimulation and Insulin-Receptor Tyrosine Kinase Activation in Iso Phillips, Nelson B., et al., “Supramolecular Protein Engineering: lated Adipocytes with a Covalent Insulin Dimer (B29.B29'- Design of Zinc-Stapled Insulin Hexamers as a Long Acting Depot.” Sunberoyl-Insulin). Biochemical Pharmacology, 1989. 38(14): p. J. Biol. 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Roberts et al., “Chemistry for Peptide and Protein PEGylation.” Cheng et al., “The Development of an Insulin-based Prodrug.” APS Advance Drug Delivery Reviews, Elsevier BV, Amsterdam, NL, vol. poster presentation, 2011. 54, No. 4, Jun. 17, 2002, pp. 459-476. Coffman et al., “Insulin-metal ion interactions: the binding of Mayer et al., Insulin Structure and Function, Peptide Science 2007. 88(5):687-713. divalent cations to insulin hexamers and tetramers and the assembly Mroz, Piotr et al., “Bioactivity of Insulin Analogs with Altered of insulin-hexamers.” Biochemistry, Aug. 9, 1988, vol. 27, No. 16. B-Chain Secondary Structure.” APS poster presentation. pp. 6179-6187. O'Brien, Assay for DPPIV Activity using a Homogenous, Lumines De et al., Synthesis and characterization of ester-based prodrugs of cent Method, Cell Notes, 2005, 11:8-11 (http://www.promega.com/ glucagon-like peptide 1. 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