Novel 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors: A patent review

Expert Opinion on Therapeutic Patents

Volumn 21, Issue 2, 2011, Pages 187-203

  Pfefferkorn, Jeffrey A ^a  

^a PFIZER INC   (United States)

Author keywords

Cardiovascular disease; coronary heart disease; HMG CoA reductase; hypercholesterolemia; hyperlipidemia; statins

Indexed keywords

7 [4 (4 FLUOROPHENYL) 6 ISOPROPYL 2 [METHYL(1 METHYL 1H 1,2,4 TRIAZOL 5 YL)AMINO] 5 PYRIMIDINYL] 3,5 DIHYDROXY 6 HEPTENOIC ACID; ATORVASTATIN; CERIVASTATIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MEVALONIC ACID; PRAVASTATIN; PYRIMIDINE; PYRIMIDINONE DERIVATIVE; ROSUVASTATIN; SIMVASTATIN;

CARDIOVASCULAR DISEASE; CHOLESTEROL SYNTHESIS; DRUG EFFICACY; DRUG TOLERABILITY; HUMAN; HYPERCHOLESTEROLEMIA; ISCHEMIC HEART DISEASE; MORTALITY; NONHUMAN; PATIENT ASSESSMENT; PATIENT COMPLIANCE; REVIEW; RISK FACTOR; SINGLE DRUG DOSE;

ANIMALS; C-REACTIVE PROTEIN; CARDIOVASCULAR DISEASES; CHOLESTEROL, LDL; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; MEDICATION ADHERENCE; PATENTS AS TOPIC;

EID: 79952918847     PISSN: 13543776     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543776.2011.547478     Document Type: Review

References (80)

1. Gaziano JM. Global burden of cardiovascular disease. In: Braunwald E, Zipes DP, Libby P, editors, Heart disease. 6th edition. W.B. Saunders Co., Philadelphia; 2001. p. 1-18
2. American Heart Association. Heart disease and stroke statistics - 2010 update. 2010. Available from: Http://circ.ahajournals.org/cgi/reprint/ CIRCULATIONAHA.109.192667
3. Verschuren WM, Jacobs DR, Bloemberg BP, et al Serum total cholesterol and long-term coronary heart disease mortality in different cultures. Twenty-five-year follow-up of the seven countries study. JAMA 1995;274:131-6
4. Manninen V, Tenkanen L, Koskinen P, et al Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study; Implication for treatment. Circulation 1992;85:37-45
5. Wilson PW, Kannel WB, Silbershatz H, et al Clustering of metabolic factors and coronary heart disease. Arch Intern Med 1999;159:1104-9 (Pubitemid 29230863)
6. Kastelein JJP. The future of best practice. Atherosclerosis 1999;143:S17-21 (Pubitemid 29243039)
7. McKenney JM. Pharmacologic characteristics of statins. Clin Cardiol 2003;26(Suppl III):32-8
8. Tobert JA. Lovastatin and beyond: The history of the HMG-CoA reductase inhibitors. Nat Rev Drug Discov 2003;2:517-26 An excellent historical perspective on the development of statins. (Pubitemid 37361744)
9. LaRosa JC, He J, Vupputuri S. Effects of statins on risk of coronary disease. JAMA 1999;282:2340-6
10. Armitage J. The safety of statins in clinical practice. Lancet 2007;370:1781-90 (Pubitemid 350137473)
11. Zhou Q, Liao JK. Pleotropic effects of statins. Circ J 2010;74:818-26
12. Zhou Q, Liao JK. Statins and cardiovascular disease: From cholesterol lowering to pleiotropy. Curr Pharm Des 2009;15:467-78
13. Athyros VG, Kakafika AI, Tziomalos K, et al Pleotropic effects of statins - clinical evidence. Curr Pharm Des 2009;15:479-89
14. Steinberg D, Glass CK, Witztum JL. Evidence mandating earlier and more aggressive treatment of hypercholesterolemia. Circulation 2008;118:672-7
15. LaRosa JC, Grundy SM, Walters DD, et al Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-35 (Pubitemid 40471450)
16. Schwartz G, Olsson AG, Ezekowitz MD, et al Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: The MIRACL study: A randomized controlled trial. JAMA 2001;285:1711-18 (Pubitemid 32259905)
17. Cannon CP, Braunwald E, McCabe CH, et al Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504 (Pubitemid 38477774)
18. Cannon CP, Steinberg BA, Murphy SA, et al Meta-analysis of cardiovascular outcome trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 2006;48:438-45 Meta-analysis of four large trials (TNT, IDEAL, PROVE-IT and A-to-Z) revealing that aggressive lipid lowering therapy reduced the relative probability of a coronary event by 16% compared to standard therapy. (Pubitemid 44109954)
19. Grundy SM, Cleeman JI, Merz NB, et al Implications of recent clinical trials for the National Cholesterol Education Adult Treatment Panel III guidelines. Circulation 2004;110:227-39 (Pubitemid 38924592)
20. Keefe JH, Cordain L, Harris WH, et al Optimal low-density lipoprotein is 50 to 70 mg/dl. J Am Coll Cardiol 2004;43:2142-6
21. Wiviott SD, Cannon CP, Morrow DA, et al Can low-density lipoprotein be too low? The safety and efficacy of achieving very low-density lipoprotein with intensive statin therapy: A PROVE-IT-TIMI 22 sub-study. J Am Coll Cardiol 2005;46:1411-16 (Pubitemid 41446174)
22. Leeper NJ, Ardehali R, deGoma EM, et al Statin use in patients with extremely low low-density lipoprotein levels is associated with improved survival. Circulation 2007;116:613-18
23. Patel TN, Shishehbor MH, Bhatt DL. A review of high dose statin therapy: Targeting cholesterol and inflammation in atherosclerosis. Eur Heart J 2007;28:664-72 (Pubitemid 46439226)
24. McKenney JM, Jones PH, Bays HE, et al Comparative effects on lipid levels of combination therapy with a statin and extended release niacin or ezetimibe versus a statin alone (the COMPELL study). Atherosclerosis 2007;192:432-7 (Pubitemid 46726341)
25. Ridker PM, Danielson E, Fonseca FA, et al; The JUPITOR Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207
26. Ridker PM. moving toward new statin guidelines in a post-JUPITOR world: Principles to consider. Curr Atherosclerosis Rep 2009;11:249-56
27. Bates TR, Connaughton VM, Watts GF. Non-adherence to statin therapy: A major challenge for preventive cardiology. Expert Opin Pharmacother 2009;10:2973-85
28. Franc S, Dejager S, Bruckert E, et al A comprehensive description of muscle symptoms associated with lipid-lowering drugs. Cardiovasc Drugs Ther 2003;17:459-65 (Pubitemid 38339916)
29. Baer AN, Wortmann RL. Myotoxicity associated with lipid-lowering drugs. Curr Opin Rheumatol 2007;19:67-73 A comprehensive review of possible mechanisms of statin-induced myalgia as well as the clinical manifestations and management of these muscle related side effects. (Pubitemid 44885730)
30. Tiwari A, Bansal V, Chugh A, et al Statins and myotoxicity: A therapeutic limitation. Expert Opin Drug Saf 2006;5:651-66 (Pubitemid 44322883)
31. Omar MA, Wilson JP, Cox TS. Rhabdomyolysis and HMG-CoA reductase inhibitors. Ann Pharmacother 2001;35:1096-107 (Pubitemid 32880030)
32. Brukert E, Hayem G, Dejager S, et al Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients-The PRIMO study. Cardiovasc Drugs Ther 2005;19:403-14 (Pubitemid 43228152)
33. Athar H, Shah AR, Thompson PD. Possible mechanisms for statin myopathy and its relationship to physical exercise. Future Lipidol 2006;1:143-51
34. Hamelin BA, Turgeon J. Hydrophilicity/ lipophilicity: Relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharm Sci 1998;19:26-37 A review on how the physical properties of HMG-CoA reductase inhibitors influence tissue distribution and myalgia risk. (Pubitemid 28094090)
35. Pfefferkorn JA. Muscle sparing statins: Preclinical profiles and future clinical use. Curr Opin Invest Drugs 2009;10:245-52 A review on the design and early clinical evaluation of hepatoselective statins.
36. Bristol-Myers Squibb Co. HMG-CoA reductase inhibitors and method. US20020094977; 2002
37. Bristol-Myers Squibb Co. HMG-CoA reductase inhibitors and method. WO2005051386; 2005
38. Bristol-Myers Squibb Co. Pyrimidine and pyridine derivatives useful as HMG-CoA reductase inhibitors and methods for the preparation thereof. WO2005030758; 2005
39. Ahmad S, Madsen CS, Stein PD, et al (3R,5S,E)-7-(4-(4-Fluorophenyl)-6- isopropyl-2-(methyl(1-methyl-1H-1,2,4- triazol-5-yl)amino)pyrimidin-5-yl)-3,5- dihydroxyhept-6-enoic acid (BMS- 644950): A rationally designed orally efficacious 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor with reduced myotoxicity potential. J Med Chem 2008;51:2722-33 (Pubitemid 351620794)
40. Madsen CS, Janovitz E, Cuff CC, et al The guinea pig as a preclinical model for demonstrating the efficacy and safety of statins. J Pharmacol Exp Ther 2008;324:576-86 (Pubitemid 351185833)
41. Martin PD, Mitchell PD, Schneck DW. Pharmacodynamic effects and pharmacokinetics of a new HMG-CoA reductase inhibitor, rosuvastatin, after morning or evening administration in healthy volunteers. Br J Clin Pharmacol 2002;54:472-7 (Pubitemid 35356872)
42. Pfizer (Warner-Lambert Co.). Novel imidazoles. US20050239857; 2005
43. Pfefferkorn JA, Litchfield J, Hutchings R, et al Discovery of novel hepatoselective HMG-CoA reductase inhibitors for treating hypercholesterolemia: A bench-to-bedside case study on tissue selective drug distribution. Bioorg Med Chem Lett 2010; In press
44. Pfizer (Warner-Lambert Co.). Imidazole-based HMG-CoA reductase inhibitors. WO2005079790; 2005
45. Pfizer (Warner-Lambert Co.). Novel pyrazole-based HMG CoA reductase inhibitors. US20060111422; 2006
46. Pfefferkorn JA, Choi C, Larsen SD, et al Substituted pyrazoles as hepatoselective HMG-CoA reductase inhibitors: Discovery of (3R,5R)-7-[2-(4- fluoro-phenyl)-4-isopropyl-5-(4-methylbenzylcarbamoyl)- 2H-pyrazol-3-yl]- 3,5-dihydroxyheptanoic acid (PF- 3052334) as a candidate for the treatment of hypercholesterolemia. J Med Chem 2008;51:31-45
47. Pfefferkorn JA, Choi C, Larsen SD, et al Pyrazoles as hepatoselective HMG-CoA reductase inhibitors: Discovery and early clinical evaluation of PF-3052334 for the treatment of hypercholesterolemia. 31st National Medicinal Chemistry Symposium, 15 - 19 June 2008; Pittsburgh, PA; 2008. p. NMCS-124
48. Pfizer (Warner-Lambert Co.). Oxypyrazoles HMG-CoA reductase inhibitors. WO2006087630; 2006
49. Larsen SD, Poel T-J, Filipski KJ, et al Pyrazole inhibitors of HMG-CoA reductase: An attempt to dramatically reduce synthetic complexity through minimal analog redesign. Bioorg Med Chem Lett 2007;17:5567-72 (Pubitemid 47391323)
50. Pfizer (Warner-Lambert Co.). N-Alkyl pyrroles as HMG-CoA reductase inhibitors. WO2005056004; 2005
51. Pfefferkorn JA, Song Y, Sun KL, et al Design and synthesis of hepatoselective, pyrrole-based HMG-CoA reductase inhibitors. Bioorg Med Chem Lett 2007;17:4538-44 (Pubitemid 47058950)
52. Bratton L, Auerbach B, Choi C, et al Discovery of pyrrole-based hepatoselective ligands as potent inhibitors of HMG-CoA reductase. Bioorg Med Chem 2007;15:5576-89 (Pubitemid 46962987)
53. Pfefferkorn JA, Bowles DM, Kissel W, et al Development of a practical synthesis of novel, pyrrole-based HMG-CoA reductase inhibitors. Tetrahedron 2007;63:8124-34 (Pubitemid 47031254)
54. Pfizer (Warner-Lambert Co.). Fused bicyclic pyrroles as HMG-CoA reductase inhibitors. WO2006059210; 2006
55. Pfefferkorn JA, Choi C, Song Y, et al Design and synthesis of novel, conformationally restricted HMG-CoA reductase inhibitors. Bioorg Med Chem Lett 2007;17:4531-7 (Pubitemid 47058951)
56. Pfizer (Warner-Lambert Co.). Novel pyrrole-based HMG-CoA reductase inhibitors. US20050043364; 2005
57. Park WKC, Kennedy RM, Larsen SD, et al Hepatoselectivity of statins: Design and synthesis of 4-sulfamoyl pyrroles as HMG-CoA reductase inhibitors. Bioorg Med Chem Lett 2008;18:1151-6 (Pubitemid 351179323)
58. Ranbaxy Pharmaceuticals. Substituted pyrrole derivatives. US20040102511; 2004
59. Ranbaxy Pharmaceuticals. Substituted pyrrole derivatives as HMG-CoA reductase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cholesterol-related diseases. US20070149605; 2007
60. Ranbaxy Pharmaceuticals. Substituted pyrrole derivatives as HMG-CoA reductase inhibitors. WO2004105752; 2004
61. Ranbaxy Pharmaceuticals. Substituted pyrrole derivatives and their use as HMG-CoA inhibitors. US20100056602; 2010
62. Shanghai Institute of Pharmaceutical Industry. Quinoline compounds, pharmaceutical compositions, Preparation methods and uses thereof. WO2009132593; 2009
63. Cai Z, Zhou W, Sun L. Synthesis and HMG CoA reductase inhibition of 4-thiophenyl quinolines as potential hypocholesterolemic agents. Bioorg Med Chem 2007;15:7809-29 (Pubitemid 47575908)
64. Zhao S, Zhou W, Liu J. Synthesis and HMG-CoA reductase inhibition of 2-cyclopropyl-4-thiophenyl quinoline mevalonalactones. Bioorg Med Chem 2009;17:7915-23
65. Wang S, Yao H. Preparation of pyrimidine derivatives as HMG-CoA reductase inhibitors. CN200410069193; 2004
66. Wang S. Preparation of 2-pyridinone derivatives as HMG-CoA reductase inhibitors. CN200410102714; 2004
67. Yao H. Preparation of pyrimidinone derivatives as HMG-CoA reductase inhibitors. WO2006066512; 2006
68. Hosoda S, Matsuda D, Tomoda H, et al Application of a 3,3-diphenylpentane skeleton as a multi-template for creation of HMG-CoA reductase inhibitors. Bioorg Med Chem Lett 2009;19:4228-31
69. Beri A, Sural N, Mahajan SB. Non-atheroprotective effects of statins. Am J Cardiovasc Drugs 2009;9:361-70
70. Campbell CY, Rivera JJ, Blumenthal RS. Residual risk in statin-treated patients: Future therapeutic options. Curr Cardiol Rep 2007;9:499-505 (Pubitemid 350081422)
71. Ansell BJ, Fonarow GC, Maki KC, et al Reduced treatment success in lipid management among women with coronary heart disease or risk equivalents: Results of a national survey. Am Heart J 2006;152:976-81 (Pubitemid 44637134)
72. Waters DD, Brotons C, Chiang CW, et al Lipid treatment assessment project 2. A multinational survey to evaluate the proportion of patients achieving low-density lipoprotein treatment goals. Circulation 2009;120:28-34
73. Franks P, Tancredi D, Winters P, Fiscella K. Cholesterol treatment with statins: Who is left out and who makes it to goal? BMC Health Serv Res 2010;10:68. Available from: Http:// www.biomedcentral.com/content/ pdf/1472-6963-10-68.pdf
74. Cannon CP, Guigliano RP, Blazing MA, et al Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): Comparison of ezetimibe/ simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Am Heart J 2008;156:826-32
75. Paras C, Hussain MM, Rosenson RS. Emerging drugs for hyperlipidemia. Expert Opin Emerg Drugs 2010;15:433-51
76. Tavridou A, Manolopoulos VG. Novel molecules targeting dyslipidemia and atherosclerosis. Curr Med Chem 2008;15:792-802 (Pubitemid 351516796)
77. Kastelein JJ, Akdim F, Stroes ES. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1432-43
78. Taylor AJ, Villines TC, Stanek EJ, et al Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med 2009;361:2113-22
79. O'Keefe JH, Bybee KA, Lavie CJ. Intensive lipid intervention in the post-ENHANCE era. Mayo Clin Proc 2008;83:867-9
80. Padial LR. The ENHANCE trial: Analysis and clinical significance. Clin Lipidol 2010;5:161-6