Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4 -hydroxyphenyl)-2-azetidinone (SCH 58235): a designed, potent, orally active inhibitor of cholesterol absorption

Journal of Medicinal Chemistry
S B RosenblumD A Burnett

Abstract

(3R)-(3-Phenylpropyl)-1,(4S)-bis(4-methoxyphenyl)-2-azetidinone (2, SCH 48461), a novel inhibitor of intestinal cholesterol absorption, has recently been described by Burnett et al. and has been demonstrated to lower total plasma cholesterol in man. The potential sites of metabolism of 2 were considered, and the most probable metabolites were prepared. The oral cholesterol-lowering efficacy of the putative metabolites was evaluated in a 7-day cholesterol-fed hamster model for the reduction of serum total cholesterol and liver cholesteryl esters versus control. On the basis of our analysis of the putative metabolite structure-activity relationship (SAR), SCH 58235 (1, 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)- (4-hydroxyphenyl)-2-azetidinone) was designed to exploit activity enhancing oxidation and to block sites of potential detrimental metabolic oxidation. Additionally, a series of congeners of 2 were prepared incorporating strategically placed hydroxyl groups and fluorine atoms to further probe the SAR of 2-azetidinone cholesterol absorption inhibitors. Through the SAR analysis of a series of putative metabolites of 2, compound 1 was targeted and found to exhibit remarkable efficacy with an ED50 of ...Continue Reading

References

Jun 10, 1994·Journal of Medicinal Chemistry·D A BurnettJ W Clader
May 10, 1996·Journal of Medicinal Chemistry·P A McCarthyM P Zawistoski
Jun 1, 1996·The American Journal of Medicine·J J Marcelino, K R Feingold
Aug 1, 1997·Journal of Medicinal Chemistry·M P DeNinnoL M Zaccaro

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Citations

Aug 10, 2001·Chemistry : a European Journal·M AvalosG Silvero
Aug 7, 2002·Current Atherosclerosis Reports·Margaret E Brousseau, Ernst J Schaefer
Dec 17, 2008·Current Atherosclerosis Reports·Michael H Davidson
Oct 14, 2008·Genes & Nutrition·C Martini, V Pallottini
Nov 8, 2003·Clinical Therapeutics·LilyAnn Jeu, Judy W M Cheng
Jan 30, 2002·Bioorganic & Medicinal Chemistry Letters·Duane A BurnettJohn W Clader
Jan 30, 2002·Bioorganic & Medicinal Chemistry Letters·Duane A BurnettJohn W Clader
Mar 23, 2012·Chemical Reviews·Alexander DömlingKan Wang
Jan 12, 2010·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Glenn P LoboJohannes von Lintig
Sep 13, 2012·Acta Crystallographica. Section E, Structure Reports Online·Feng ZhangGuo Kai
Mar 27, 2001·Annual Review of Pharmacology and Toxicology·B K ParkP M O'Neill
Sep 28, 2006·Annual Review of Physiology·David Q-H Wang
Jul 24, 2010·American Journal of Physiology. Gastrointestinal and Liver Physiology·Li YangPatrick Tso
Aug 15, 2012·Journal of Lipid Research·Makoto KuranoKazuhisa Tsukamoto
Aug 23, 2012·Vascular Health and Risk Management·Binh An P PhanPeter P Toth
Oct 25, 2002·Drugs·Thomas Sudhop, Klaus von Bergmann
Oct 10, 2012·Future Medicinal Chemistry·Neha K Grewal, Nicholas E Leadbeater
Nov 1, 2009·Future Medicinal Chemistry·David J Newman, Gordon M Cragg
Feb 27, 2004·Proceedings of the National Academy of Sciences of the United States of America·Eric J SmartSteven A Farber
Sep 3, 2010·Annual Review of Physiology·Lin JiaLiqing Yu
Oct 16, 2003·Current Cardiology Reports·Michael H Davidson
Mar 20, 2004·Expert Review of Cardiovascular Therapy·Michael H Davidson
Nov 30, 2004·Expert Opinion on Investigational Drugs·Christopher J Boos, Gregory Y H Lip
Jun 1, 2007·Expert Opinion on Drug Discovery·Matthias Adam
Jul 3, 2015·Journal of Enzyme Inhibition and Medicinal Chemistry·Babita AnejaMohammad Abid
Mar 12, 2016·Journal of Chromatographic Science·Lili SunPingkai Ouyang
Oct 16, 2015·Journal of Medicinal Chemistry·Francisco Lopez-TapiaAndré Alker
Aug 2, 2011·Expert Opinion on Therapeutic Targets·Ronald Pj Oude Elferink, Ulrich Beuers
Nov 2, 2013·Journal of Pharmaceutical and Biomedical Analysis·Srikanth GuntupalliAminul Islam
Jul 26, 2014·Saudi Pharmaceutical Journal : SPJ : the Official Publication of the Saudi Pharmaceutical Society·Prasad G JamkhandeRam S Sakhare
Jul 8, 2008·Atherosclerosis·Hironori NakagamiRyuichi Morishita
May 29, 2015·Biotechnology, Biotechnological Equipment·Irfan PervaizWajahat Mahmood
Apr 15, 2016·Molecular Biology of the Cell·Tory A Johnson, Suzanne R Pfeffer
May 29, 2007·Digestive and Liver Disease : Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver·F LiguoriS Ginanni Corradini
Feb 12, 2017·The Journal of Organic Chemistry·Harekrishna SahooMahiuddin Baidya

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