Modulation of 11beta-hydroxysteroid dehydrogenase type 1 activity by 1,5-substituted 1H-tetrazoles.
Inhibitors of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) show promise as drugs to treat metabolic disease and CNS disorders such as cognitive impairment. A series of 1,5-substituted 1H-tetrazole 11beta-HSD1 inhibitors has been discovered and chemically modified. Compounds are selective for 11beta-HSD1 over 11beta-HSD2 and possess good cellular potency in human and murine 11beta-HSD1 assays. A range of in vitro stabilities are observed in human liver microsome assays.
Webster
Scott P
SP
Endocrinology Unit, Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. scott.webster@ed.ac.uk
Binnie
Margaret
M
McConnell
Kirsty M M
KM
Sooy
Karen
K
Ward
Peter
P
Greaney
Michael F
MF
Vinter
Andy
A
Pallin
T David
TD
Dyke
Hazel J
HJ
Gill
Matthew I A
MI
Warner
Ines
I
Seckl
Jonathan R
JR
Walker
Brian R
BR
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D013777:Tetrazoles / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D013777:Tetrazoles; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1
Bioorg Med Chem Lett. 2009 Jul 1;19(13):3493-7
19473839
Endocrinology. 2001 Apr;142(4):1371-6
11250914
Bioorg Med Chem Lett. 2005 Oct 1;15(19):4359-62
16039856
J Exp Med. 2005 Aug 15;202(4):517-27
16103409
J Clin Endocrinol Metab. 2003 Dec;88(12):5593-602
14671138
Diabetes Obes Metab. 2009 Jul;11(7):688-99
19527482
Expert Opin Drug Discov. 2007 Jan;2(1):131-44
23496041
Bioorg Med Chem. 2007 Jul 1;15(13):4396-405
17490884
J Biol Chem. 2001 Nov 2;276(44):41293-300
11546766
Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4716-21
11274359
J Pharmacol Exp Ther. 2008 Jan;324(1):299-305
17921190
Eur J Clin Invest. 2009 Feb;39(2):81-93
19200161
Exp Gerontol. 1995 May-Aug;30(3-4):229-51
7556505
Expert Opin Ther Pat. 2009 Jun;19(6):801-25
19456274
J Chem Inf Model. 2006 Mar-Apr;46(2):665-76
16562997
Eur J Endocrinol. 2007 Nov;157(5):545-59
17984234
Ageing Res Rev. 2005 May;4(2):141-94
15996533
Front Horm Res. 2008;36:146-164
18230901
Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14924-9
9405715
J Med Chem. 2007 Feb 8;50(3):429-32
17266194
Bioorg Med Chem Lett. 2006 Oct 15;16(20):5414-9
16899366