title: Carboxylesterase inhibitors.
abstract: BACKGROUND
  Carboxylesterases play major roles in the hydrolysis of numerous therapeutically active compounds. This is, in part, due to the prevalence of the ester moiety in these small molecules. However, the impact these enzymes may play on drug stability and pharmacokinetics is rarely considered prior to molecule development. Therefore, the application of selective inhibitors of this class of proteins may have utility in modulating the metabolism, distribution and toxicity of agents that are subjected to enzyme hydrolysis.
  
  
  METHODS
  This review details the development of all such compounds dating back to 1986, but principally focuses on the very recent identification of selective human carboxylesterases inhibitors.
  
  
  CONCLUSIONS
  The implementation of carboxylesterase inhibitors may significantly revolutionize drug discovery. Such molecules may allow for improved efficacy of compounds inactivated by this class of enzymes and/or reduce the toxicity of agents that are activated by these proteins. Furthermore, since lack of carboxylesterase activity appears to have no obvious biological consequence, these compounds could be applied in combination with virtually any esterified drug. Therefore, inhibitors of these proteins may have utility in altering drug hydrolysis and distribution in vivo. The characteristics, chemical and biological properties and potential uses of such agents are discussed here.
authors: Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
authors: M Jason
authors: MJ
authors: Hatfield
authors: Philip M
authors: PM
authors: Potter
references: Neurotoxicology. 2000 Feb-Apr;21(1-2):223-7
references: 10794404
references: Biochem Pharmacol. 1998 May 1;55(9):1419-26
references: 10076534
references: Mol Pharmacol. 2004 Jun;65(6):1336-43
references: 15155827
references: Life Sci. 1996;58(15):1201-7
references: 8614273
references: Biochemistry. 1985 Apr 9;24(8):1813-7
references: 2990541
references: J Pharmacol Exp Ther. 2004 Aug;310(2):469-76
references: 15082749
references: Drug Metab Dispos. 2004 Oct;32(10):1103-10
references: 15269188
references: J Med Chem. 2005 Apr 21;48(8):2906-15
references: 15828829
references: J Med Chem. 2009 Jun 25;52(12):3742-52
references: 19534556
references: Mol Pharmacol. 2007 Mar;71(3):713-23
references: 17167034
references: J Nat Prod. 2002 Aug;65(8):1173-6
references: 12193025
references: Curr Top Med Chem. 2007;7(6):557-68
references: 17352677
references: Cancer Res. 2000 Aug 1;60(15):4206-10
references: 10945631
references: Chem Biol Interact. 2008 Sep 25;175(1-3):3-10
references: 18586019
references: J Mol Biol. 2006 Oct 13;363(1):201-14
references: 16962139
references: Biol Pharm Bull. 1995 May;18(5):648-52
references: 7492976
references: Dementia. 1996 Nov-Dec;7(6):293-303
references: 8915035
references: Biochemistry. 1986 Jul 1;25(13):3760-7
references: 3527255
references: J Mol Biol. 2005 Sep 9;352(1):165-77
references: 16081098
references: Chem Biol. 2003 Apr;10(4):341-9
references: 12725862
references: Res Commun Mol Pathol Pharmacol. 1995 Apr;88(1):87-97
references: 7620841
references: Biochem Pharmacol. 1969 Apr;18(4):801-11
references: 5788519
references: J Med Chem. 2010 Dec 23;53(24):8709-15
references: 21105730
references: Mol Pharmacol. 2010 Apr;77(4):508-16
references: 20051531
references: Drug Discov Today. 2005 Mar 1;10(5):313-25
references: 15749280
references: Biochem Soc Trans. 2003 Jun;31(Pt 3):620-4
references: 12773168
references: Cancer Res. 2000 Mar 1;60(5):1189-92
references: 10728672
references: J Mol Biol. 1992 Aug 20;226(4):1085-99
references: 1518046
references: Chem Res Toxicol. 1992 Sep-Oct;5(5):680-4
references: 1446009
references: Comp Biochem Physiol B Biochem Mol Biol. 2010 May;156(1):6-11
references: 20117228
references: Toxicol Appl Pharmacol. 2007 May 15;221(1):1-12
references: 17442360
references: Insect Biochem Mol Biol. 2008 Oct;38(10):940-9
references: 18721883
references: Drug Discov Today. 2002 Aug 1;7(15):807-14
references: 12546968
references: Ann Oncol. 1996 Oct;7(8):837-42
references: 8922198
references: J Med Chem. 2007 Apr 19;50(8):1876-85
references: 17378546
references: Pest Manag Sci. 2010 Oct;66(10):1096-100
references: 20582994
references: Environ Toxicol. 2010 Dec;25(6):601-7
references: 19565633
references: Biochemistry. 1990 Aug 21;29(33):7608-17
references: 2271521
references: Br J Pharmacol. 2010 Aug;160(8):1916-28
references: 20649590
references: Chem Biol Interact. 2010 Sep 6;187(1-3):10-22
references: 20138030
references: J Biol Chem. 1997 Jun 6;272(23):14769-75
references: 9169443
references: J Med Chem. 2005 Aug 25;48(17):5543-50
references: 16107154
references: Nat Rev Drug Discov. 2005 Sep;4(9):764-74
references: 16121130
references: J Pharmacol Exp Ther. 2005 Jun;313(3):1011-6
references: 15687373
references: J Pharmacol Exp Ther. 1996 Nov;279(2):713-7
references: 8930175
references: Drug Metab Dispos. 2002 Jun;30(6):643-7
references: 12019189
references: J Pharmacol Exp Ther. 1999 Jul;290(1):314-8
references: 10381793
references: Chem Biol Interact. 2005 Dec 15;157-158:277-83
references: 16243304
references: Mol Cancer Ther. 2006 Sep;5(9):2281-8
references: 16985062
references: Nat Struct Biol. 2003 May;10(5):349-56
references: 12679808
references: J Mol Neurosci. 2003;20(3):369-83
references: 14501022
references: Curr Top Med Chem. 2005;5(4):371-81
references: 15892680
references: J Med Chem. 1999 May 20;42(10):1723-38
references: 10346925
references: Biochem Pharmacol. 2005 Nov 25;70(11):1673-84
references: 16213467
references: Cancer Chemother Pharmacol. 2005 Dec;56(6):629-36
references: 15918039
references: Biol Pharm Bull. 1994 May;17(5):662-4
references: 7920428
references: Biochem Genet. 1994 Feb;32(1-2):9-24
references: 8031296
references: Nat Struct Biol. 2002 May;9(5):337-42
references: 11967565
references: J Nat Prod. 2002 Apr;65(4):595-7
references: 11975511
references: Chem Res Toxicol. 2001 Dec;14(12):1563-72
references: 11743738
references: Oncol Nurs Forum. 1998 Apr;25(3):535-43
references: 9568608
references: Mol Biotechnol. 2000 Nov;16(3):193-202
references: 11252804
references: Cancer Res. 2000 Sep 1;60(17):4725-8
references: 10987276
references: J Pharmacol Exp Ther. 2006 Dec;319(3):1477-84
references: 16966469
references: Biochim Biophys Acta. 2010 Jan;1801(1):31-41
references: 19761868
references: Xenobiotica. 2010 Jun;40(6):369-80
references: 20297923
references: Nature. 1969 Aug 16;223(5207):704-5
references: 4979456
references: Curr Med Chem. 2008;15(24):2433-55
references: 18855672
references: Environ Health Perspect. 1996 Mar;104 Suppl 1:23-40
references: 8722108
references: J Med Chem. 1997 Apr 25;40(9):1347-65
references: 9135032
references: Aquat Toxicol. 2010 Jan 31;96(2):115-23
references: 19879661
references: J Med Chem. 2007 Nov 15;50(23):5727-34
references: 17941623
references: Aquat Toxicol. 2007 Oct 15;84(3):328-336
references: 17688956
references: Bioorg Med Chem. 2007 Jun 1;15(11):3801-17
references: 17399985
references: Curr Med Chem. 2006;13(9):1045-54
references: 16611083
references: Science. 1973 Apr 15;180(4082):149-54
references: 4632837
references: Biochim Biophys Acta. 2008 Oct;1781(10):643-54
references: 18762277
references: J Pest Sci (2004). 2010;35(3):240-249
references: 23487487