Ezetimibe and other azetidinone cholesterol absorption inhibitors

Current Topics in Medicinal Chemistry

Volumn 5, Issue 3, 2005, Pages 243-256

  Clader, John W ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1,4 BIS(4 METHOXYPHENYL) 3 (3 PHENYLPROPYL) 2 AZETIDINONE; ALKYL GROUP; ANTILIPEMIC AGENT; AZETIDINONE DERIVATIVE; BENZENE DERIVATIVE; BENZYL DERIVATIVE; CARBOHYDRATE DERIVATIVE; CARBONYL DERIVATIVE; CARBOXYL GROUP; CHOLESTEROL; DRUG METABOLITE; EZETIMIBE; GLUCURONIDE; HYDROXYL GROUP; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LACTAM DERIVATIVE; PHENOL DERIVATIVE; PROPYLENE; SCH 47949; SPIRONOLACTONE; SULFIDE; SULFONE DERIVATIVE; SULFOXIDE; UNCLASSIFIED DRUG;

CARDIOVASCULAR RISK; CHOLESTEROL BLOOD LEVEL; CLINICAL TRIAL; CORONARY ARTERY ATHEROSCLEROSIS; CORONARY ARTERY DISEASE; DEVELOPED COUNTRY; DIETARY INTAKE; DRUG EFFICACY; DRUG EXCRETION; DRUG POTENTIATION; DRUG STABILITY; DRUG SYNTHESIS; DRUG USE; EXERCISE; HUMAN; HYPERCHOLESTEROLEMIA; LIPID ABSORPTION; NONHUMAN; REVIEW; RISK REDUCTION; STRUCTURE ACTIVITY RELATION;

ANTICHOLESTEREMIC AGENTS; AZETIDINES; CHOLESTEROL; CORONARY DISEASE; DRUG THERAPY, COMBINATION; HUMANS; INTESTINAL ABSORPTION; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 18144370832     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/1568026053544498     Document Type: Review

References (58)

1. For a recent review on lipid lowering therapy, see Bruckert, E. New Advances in Lipid-Modifying Therapies for Reducing Cardiovascular Risk. Cardiology 2002, 97, 59-66, and references contained therein.
2. (a) Shepherd, J. Clinical Experience With Ezetimibe, The First New Class Of Cholesterol Absorption Inhibitors. 73rd European Atherosclerosis Society Congress, Salburg, Austria, July 7, 2002.
3. (b) Stein, E.; Stender, S.; Mata, P.; Ponsonnet, D.; Metani, L.; Lipka, L.; Suresh, R.; Veltri, E. Coadministration Of Ezetimibe Plus Atorvastatin. 73rd European Atherosclerosis Society Congress, Salburg, Austria, July 9, 2002.
4. (c) Stein, E.A. An investigative look: selective cholesterol absorption inhibitors - embarking on a new standard of care. Am. J. Manag. Care 2002 8(2 Suppl.), S36-9, discussion S45-7.
5. (a) Schnitzer-Polokoff, R.; Compton, D.; Boykow, G.; Davis, H.; Burrier, R. Effects of acyl-CoA: cholesterol O-acyltransferase inhibition on cholesterol absorption and plasma lipoprotein composition in hamsters. Comparative Biochemistry and Physiology. A: Comparative Physiology 1991, 99, 665-670.
6. (b) Clader, J.W.; Berger, J. G.; Burrier, R.E.; Davis, H.R.; Domalski, M.; Dugar, S.; Kogan, T. P.; Salisbury, B.; Vaccaro, W. Substituted (1,2-diarylethyl)amide acyl-CoA: cholesterol acyltransferase inhibitors: Effect of polar groups on in vitro and in vivo activity. J. Med. Chem. 1995, 38, 1600-1607.
7. (a) Heinzl, S. Ezetimibe. A new cholesterol absorption inhibitor. Med. Monatsschr. Pharm.. 2002, 25, 229-232.
8. (b) Meng, C.Q. Ezetimibe. Schering-Plough. Curr. Opin. Investig. Drugs 2002 3, 427-432.
9. (c) Leitersdorf, E. Selective cholesterol absorption inhibition: a novel strategy in lipid-lowering management. Int. J. Clin. Pract. 2002 56, 116-119.
10. (d) Miettinen, T.A. Cholesterol absorption inhibition: a strategy for cholesterol-lowering therapy.Int. J. Clin. Pract. 2001, 55, 710-716.
11. Burnett, D.A.; Caplen, M.A.; Davis, H.R. Jr.; Burrier, R. E.; Clader, J.W. 2-Azetidinones as Inhibitors of Cholesterol Absorption. J. Med. Chem. 1994, 37, 1733-1736.
12. Vaccaro, W.; Amore, C.; Berger, J.; Burrier, R.; Clader, J.; Davis, H.; Domalski, M.; Fevig, T.; Salisbury, B.; Sher, R. Inhibitors of Acyl CoA:Cholesterol Acyltransferase. J. Med. Chem. 1996, 39, 1704-1719.
13. Sliskovic, D. R.; White, A. D. Therapeutic Potential of ACAT Inhibitors as Lipid Lowering and Anti-atherosclerotic Agents. Trends Pharmacol. Sci. 1991, 323, 1289-1298.
14. Salisbury, B.G.; Davis, H.R.; Burrier, R.E.; Burnett, D.A.; Boykow, G.; Caplen, M.A.; Clemmons, A.L.; Compton, D.S.; Hoos, L.M.; McGregor, D.G.; Schnitzer-Polokoff, R.; Smith, A.A.; Weig, B.C.; Zilli, D.L.; Clader, J.W.; Sybertz, E.J. Hypocholesterolemic activity of a novel inhibitor of cholesterol absorption, SCH 48461. Atherosclerosis 1995, 115, 45-63.
15. Dujovne, C.A.; Bays, H.; Davidson, M.H.; Knopp, R.; Hunninghake, D.B.; Stein, E.A.; Goldberg, A.C.; Jones, P.; Lipka, L.J.; Cuffie-Jackson, C. Reduction of LDL cholesterol in patients with primary hypercholesterolemia by SCH 48461: results of a multicenter dose-ranging study. J. Clin. Pharmacol. 2001, 41, 70-8.
16. (a) Burnett, D.A. Asymmetric Synthesis and absolute stereochemistry of Cholesterol Absorption Inhibitor, SCH 48461. Tetrahedon Lett. 1994, 35, 7339-7342.
17. (b) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F. Stereoselective synthesis of 2-azetidinones as cholesterol-absorption inhibitors. Tetrahedron: Asymmetry 1999, 10, 4841-4849.
18. (c) Thiruvengadam, T.K.; Mcallister, T.; Tann, C. Process for the synthesis of chiral azetidinones. PCT Int. Appl. WO 9501961 ( 1995)
19. (d) Thiruvengadam, T.K.; Tann, C.; Lee, J.; McAllister, T.; Sudhakar, A. Process for the stereospecific synthesis of azetidinones. US Patent 5306817 (1994)
20. (e) Braun, Manfred; Galle, Dietmar. A simple stereoselective synthesis of the cholesterol absorption inhibitor (-)-SCH 48461. Synthesis 1996, (7), 819-820.
21. (f) Burnett, D.A.; Clader, J.W.; Thiruvengadam, T.K.; Tann, C.; Lee, J.; McAllister, T.; Colon, C.; Barton, D.H.R.; Breslow, R.; Substituted beta-lactam compounds useful as hypocholesterolemic agents and processes for their preparation. Eur. Pat. Appl. EP 524595 A1 ( 1993). See also reference [22].
22. Clader, J.W.; Burnett, D.A.; Caplen, M.A.; Domalski, M.S.; Dugar, S.; Vaccaro, W.; Sher, R.; Browne, M.E.; Zhao, H.; Burrier, R.E.; Salisbury, B., Davis, H.R. Jr. 2-Azetidinone Cholesterol Absorption Inhibitors: Structure-Activity Relationships on the Heterocyclic Nucleus. J. Med. Chem. 1996, 39, 3694-3693.
23. Vaccaro, W.D.; Sher, R.; Davis, H.R. Jr. 2-Azetidinone Cholesterol Absorption Inhibitors: Increased potency by substitution of the C-4 phenyl ring. Bioorg. Med. Chem. Lett. 1996, 6, 1429-1437.
24. Van Heek, M.; France, C.F.; Compton, D.S.; McLeod, R.L.; Yumibe, N.P.; Alton, K.B.; Sybertz, E.J.; Davis, H,R. Jr. In vivo metabolism-based discovery of a potent cholesterol absorption inhibitor, SCH 58235, in the rat and rhesus monkey through identification of the active metabolites of SCH 48461. J. Pharm. Exper. Ther. 1997, 283, 157-163
25. Rosenblum, S.R. Unpublished results.
26. Yumibe, N. Unpublished results.
27. Dugar, S.; Kirkup, M.; Clader, J.W.; Lin, S.-I.; Rizvi, R.; Snow, M.E.; Davis, H.R. Jr.; McCombie, S.W. Gamma-Lactams and related compounds as Cholesterol Absorption Inhibitors: Homologs of the beta-lactam cholesterol absorption inhibitor SCH 48461. Bioorg. Med. Chem. Lett. 1995, 5, 2947-2952.
28. Rosenblum, S.B.; Huynh, T.; Afonso, A.; Davis, H.R. Jr.; Yumibe, N.; Clader, J.W.; Burnett, D.A. Discovery of I-(4-Fluorophenyl)-(3R) -[3-(4-fluorophenyl)-(3S)-hydroxypropyl]- (4S)-(4-hydroxyphenyl)-2-azetidinone (SCH 58235): A Designed, Potent,Orally Active Inhibitor of Cholesterol Absorption J. Med. Chem. 1998, 41(6), 973-980.
29. (a) Homann, M.J.; Previte, E. Stereoselective microbial reduction for the preparation of 1-(4-fluorophenyl)-3(R)-[3(S)-hydroxy-3-(4-fluorophenyl) propyl]-4(S)-(4 -hydroxyphenyl)-2-azetidinone. US Pat. Appl. 6133001 (2000)
30. (b) Thiruvengadam, T.K.; Fu, X.; Tann, C.-H.; McAllister, T.L.; Chiu, J.S.; Colon, C. Process for the synthesis of azetidinones and intermediates for use as hypocholesterolemics. PCT Int. Appl. WO 0034240 (2000)
31. (c) Wu, G.; Wong, Y.; Chen, X.; Ding, Z. A Novel One-Step Diastereo-and Enantioselective Formation of trans-Azetidinones and Its Application to the Total Synthesis of Cholesterol Absorption Inhibitors. J. Org. Chem. 1999, 64, 3714-3718
32. (d) Wu, G.; Chen, X.; Wong, Y.-S.; Schumacher, D.P.; Steinman, M. A process for the enantioselective preparation of azetidinones using 3-hydroxy gamma-lactone. US Pat. 5886171 (1999)
33. (e) Shankar, B.B. Process for preparing 1-(4-fluorophenyl)-3(R)-(3(S)-hydroxy-3-([phenyl or 4-fluorophenyl])-propyl)-4(S)-(4-hydroxyphenyl)-2-azetidinone. US Pat. 5856473 (1999)
34. (f) Wu, G.-Z.; Chen, X.; Wong, Y.-S.; Schumacher, D.P.; Steinman, M. 3-Hydroxy gamma-lactone based enantioselective synthesis of azetidinones. PCT Int. Appl. WO 9745406 A1 (1997). See also references [17] and [22].
35. McKittrick, B.A.; Ma, K.; Dugar, S.; Clader, J.W.; Davis, H. Jr., Czarniecki, M. Stereoselective Synthesis and Biological Activity of CIS Azetidinones as Cholesterol Absorption Inhibitors. Bioorg. Med. Chem. Lett. 1996, 6, 1947-1950.
36. Dugar, S.; Yumibe, N.; Clader, J.W.; Vizziano, M.; Huie, K.; Van Heek, M.; Compton, D.S.; Davis, H.R. Jr. Metabolism and Structure Activity Data Based Design: Discovery of (-) SCH 53079. An Analog of the Potent Cholesterol Absorption Inhibitor (-) SCH 48461. Bioorg. Med. Chem. Lett. 1996, 6, 1271-1274.
37. Kirkup, M.P.; Rizvi, R.; Shankar, B.; Dugar, S.; Clader, J.W.; McCombie, S.W.; Lin, S-I.; Yumibe, N. (-)-SCH 57939: synthesis and pharmacological properties of a potent, metabolically stable cholesterol absorption inhibitor.Bioorg. Med. Chem. Lett. 1996, 6, 2069-2072.
38. Shankar, B. B.; Kirkup, M. P.; McCombie, S. W.; Clader, J. W.; Ganguly, A. K. Synthesis of an Optically Pure 3-Unsubstituted β-Lactam Using an Asymmetric Reformatsky Reaction and its Conversion to Cholesterol Absorption Inhibitors. Tetrahedron Lett. 1996, 37, 4095-4098.
39. McKittrick, B.A.; Ma, K.; Huie, K.; Yumibe, N.; Davis, H.R. Jr., Clader, J.W.; Czarniecki, M.; McPhail, AT. Synthesis of C3 Heteroatom-Substituted Azetidinones That Display Potent Cholesterol Absorption Inhibitory Activity, J. Med. Chem. 1998, 41, 752-759
40. Dugar, S. unpublished results. For a related series of unsaturated analogs
41. see Rosenblum, S.R.; Huynh, T.; Afonso, A.; Davis, H.R. Jr. Synthesis of 3-arylpropenyl, 3-arylpropynyl, and 3-arylpropyl 2-azetidinones as Cholesterol Absorption Inhibitors: Application of the palladium-catalyzeed arylation of alkenes and alkynes. Tetrahedron 2000, 56, 5735-5742.
42. Dugar, S.; Clader, J.W.; Chan, T-M.; Davis H.R. Jr. Substituted 2-Azaspiro [5.3]nonan-1-ones as Potent Cholesterol Absorption Inhibitors: Defining a Binding Conformation of SCH 48461. J. Med. Chem. 1995, 38, 4875-4877.
43. Domalski, M.S.; Clader, J.W. unpublished results.
44. (a) Chen, Li-Y.; Zaks, A.; Chackalamannil, S.; Dugar, S.. Asymmetric Synthesis of substituted 2-azaspiro[3.5]nonan-1-ones: An enantioselective Synthesis of the Cholesterol Absorption Inhibitor (+)-SCH 54016.
45. (b) Wu, G.; Tormos, W. A catalytic asymmetric synthesis of a spirofused azetidinone as a cholesterol absorption inhibitor. J. Org. Chem. 1997, 62, 6412-6414.
46. (b) Wu, G.; Tormos, W. A Catalytic Asymmetric Synthesis of a Spirofused Azetidinone as a Cholesterol Absorption Inhibitor. J. Org. Chem. 1997, 62, 6412-6414.
47. (a) Vaccaro, W.D.; Sher, R., Davis, H.R. Jr. Sugar-substituted 2-azetidinones as cholesterol absorption inhibitors: Bioorg. Med. Chem. Lett. 1998, 8, 35-40.
48. (b) Vaccaro, W.D.; Davis, H.R. Jr. Sugar-substituted 2-azetidinone cholesterol absorption inhibitors: Enhanced potency by modification of the sugar. Bioorg. Med. Chem. Lett. 1998, 8, 313-318.
49. Van Heek, M.; Farley, C.; Compton, D.S.; Hoos, L.; Alton, K.B.; Sybertz, E.J.; Davis, H.R. Jr. Comparison of the Activity and disposition of the novel cholesterol absorption inhibitor, SCH 58235, and its glucuronide, SCH 60663, British J. Pharm. 2000, 129, 1748-1754
50. Vaccaro, W.D.; Sher, R., Davis, H.R. Jr. Carboxy-substituted 2-azetidinones as cholesterol absorption inhibitors. Bioorg. Med. Chem. Lett. 1998, 8, 319-322.
51. Tomiyama, H.; Yokota, M.; Noda, A.; Ohno, A. Preparation of beta-lactam compounds as serum cholesterol-lowering agents. PCT Appl WO-0266464 (2002).
52. Glombik, H.; Kramer, W.; Flohr, S.; Frick; W.; Heuer, H.; Jaehne, G.; Lindenschmidt, A.; Schaefer, H-L. Novel diphenylazetidinone compounds useful for the treatment of hyperlipidemia, arteriosclerosis and insulin resistance. PCT Pat. Appl WO-00250060 June 27, 2002. See also WO-00250068.
53. Davis, H.R. Jr.; Pula, K.K.; Alton, K.B.; Burrier, R.E.; Watkins, R.W. The Synergistic hypocholesterolemic activity of the potent cholesterol absorption inhibitor, ezetimibe, in combination with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in dogs. Metabol. Clin. Exper. 2000, 50, 1234-1241
54. (a) Burnett, D.A.; Caplen, M.A.; Domalski, M.S.; Browne, M.E.; Davis, H.R.; Clader, J.W. Synthesis of iodinated biochemical tools related to the 2-azetidinone class of cholesterol.absorption inhibitors. Bioorg. Med. Chem. Lett. 2002, 12, 311-314.
55. (b) Burnett, D.A.; Caplen, M.A.; Browne, M.E.; Zhao, H.; Altmann, S.W.; Davis, H.R.; Clader, J.W. Synthesis of fluorescent biochemical tools related to the 2-azetidinone class of cholesterol absorption inhibitors. Bioorg. Med. Chem. Lett. 2002 12, 315-318.
56. Kramer, W.; Glombik, H.; Petry, S.; Heuer, H.; Schafer, H.; Wendler, W.; Corsiero, D.; Girbig, F.; Weyland, C. Identification of binding proteins for cholesterol absorption inhibitors as components of the intestinal cholesterol transporter. FEBS Lett. 2000, 487, 293-2977.
57. Altmann, S.W.; Davis, H.R. Jr.; Zhu, L-j.; Yao, X.; Hoos, L.M.; Tetzloff, G.; Iyer, S.P.N.; Maguire, M.; Golovko, A.; Zeng, M.; Wang, L.; Murgolo, N.; Graziano, M.P. Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption. Science 2004, 303(5661), 1201-1204
58. Davis, H.R. Jr.; Zhu, Li-ji; Hoos, Lizbeth M.; Tetzloff, Glen; Maguire, Maureen; Liu, Jianjun; Yao, Xiaorui; Iyer, Sai Prasad N.; Lam, My-Hanh; Lund, Erik G.; Detmers, P.A.; Graziano, M.P.; Altmann, S.W. Niemann-Pick C1 Like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis. Journal of Biological Chemistry 2004, 279(32), 33586-33592.