Synthesis and structure-activity relationship of 2-adamantylmethyl tetrazoles as potent and selective inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)

被引：16

作者：

Ye, Xiang-Yang ^{[1
]}

Yoon, David ^{[1
]}

Chen, Stephanie Y. ^{[1
]}

Nayeem, Akbar ^{[2
]}

Golla, Rajasree ^{[3
]}

Seethala, Ramakrishna ^{[3
]}

Wang, Mengmeng ^{[4
]}

Harper, Timothy ^{[4
]}

Sleczka, Bogdan G. ^{[5
]}

Apedo, Atsu ^{[5
]}

Li, Yi-Xin ^{[5
]}

He, Bin ^{[6
]}

Kirby, Mark ^{[6
]}

Gordon, David A. ^{[6
]}

Robl, Jeffrey A. ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Res & Dev, Dept Chem, Princeton, NJ 08543 USA

[2] Bristol Myers Squibb Co, Res & Dev, CADD, Princeton, NJ 08543 USA

[3] Bristol Myers Squibb Co, Res & Dev, Lead Evaluat, Princeton, NJ 08543 USA

[4] Bristol Myers Squibb Co, Res & Dev, MAP, Princeton, NJ 08543 USA

[5] Bristol Myers Squibb Co, Res & Dev, BDAS, Princeton, NJ 08543 USA

[6] Bristol Myers Squibb Co, Res & Dev, Dept Biol, Princeton, NJ 08543 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 02期

关键词：

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1); Enzyme inhibitor; Structure-activity relationships (SAR); METABOLIC SYNDROME; PIPERAZINE SULFONAMIDES; REDUCES ATHEROSCLEROSIS; MICE; DISEASE; OBESITY; MODEL; MECHANISMS; DISCOVERY; DESIGN;

D O I：

10.1016/j.bmcl.2013.11.066

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 2-adamantylmethyl tetrazoles bearing a quaternary carbon at the 2-position of the adamantane ring (i.e. structure A) have been designed and synthesized as novel, potent, and selective inhibitors of human 11 beta-HSD1 enzyme. Based on the SAR and the docking experiment, we report for the first time a tetrazole moiety serving as the active pharmacophore for inhibitory activity of 11 beta-HSD1 enzyme. Optimization of two regions of A, R-1 and R-2 respectively, was explored with a focus on improving the inhibitory activity (IC50) and the microsomal stability in both human and mouse species. These efforts led to the identification of 26, an orally bioavailable inhibitor of human 11 beta-HSD1 with a favorable development profile. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：654 / 660

页数：7

共 34 条

[1] 11β-HSD1 Inhibitors for the Treatment of Type 2 Diabetes and Cardiovascular Disease
Anderson, Anna
Walker, Brian R.
[J]. DRUGS, 2013, 73 (13) : 1385 - 1393
[2] 1,1-Dioxo-5,6-dihydro-[4,1,2]oxathiazines, a novel class of 11β-HSD1 inhibitors for the treatment of diabetes
Boehme, Thomas
Engel, Christian K.
Farjot, Geraldine
Guessregen, Stefan
Haack, Torsten
Tschank, Georg
Ritter, Kurt
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (16) : 4685 - 4691
[3] 11β-hydroxysteroid dehydrogenase type 1 inhibitors: a review of recent patents
Boyle, Craig D.
Kowalski, Timothy J.
[J]. EXPERT OPINION ON THERAPEUTIC PATENTS, 2009, 19 (06) : 801 - 825
[4] 3 SYNTHETIC ROUTES TO A STERICALLY HINDERED TETRAZOLE - A NEW ONE-STEP MILD CONVERSION OF AN AMIDE INTO A TETRAZOLE
DUNCIA, JV
PIERCE, ME
SANTELLA, JB
[J]. JOURNAL OF ORGANIC CHEMISTRY, 1991, 56 (07) : 2395 - 2400
[5] 11β-Hydroxysteroid Dehydrogenase Type 1 Gene Knockout Attenuates Atherosclerosis and In Vivo Foam Cell Formation in Hyperlipidemic apoE-/- Mice
Garcia, Ricardo A.
Search, Debra J.
Lupisella, John A.
Ostrowski, Jacek
Guan, Bo
Chen, Jian
Yang, Wen-Pin
Amy Truong
He, Aiqing
Zhang, Rongan
Yan, Mujing
Hellings, Samuel E.
Gargalovic, Peter S.
Ryan, Carol S.
Watson, Linda M.
Langish, Robert A.
Shipkova, Petia A.
Carson, Nancy L.
Taylor, Joseph R.
Yang, Richard
Psaltis, George C.
Harrity, Thomas W.
Robl, Jeffrey A.
Gordon, David A.
[J]. PLOS ONE, 2013, 8 (02):
[6] 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors as Promising Therapeutic Drugs for Diabetes: Status and Development
Ge, R.
Huang, Y.
Liang, G.
Li, X.
[J]. CURRENT MEDICINAL CHEMISTRY, 2010, 17 (05) : 412 - 422
[7] Modulation of 11β-Hydroxysteroid Dehydrogenase as a Strategy to Reduce Vascular Inflammation
Hadoke, Patrick W. F.
Kipari, Tiina
Seckl, Jonathan R.
Chapman, Karen E.
[J]. CURRENT ATHEROSCLEROSIS REPORTS, 2013, 15 (05)
[8] Synthesis and biological analysis of benzazol-2-yl piperazine sulfonamides as 11β-hydroxysteroid dehydrogenase 1 inhibitors
Hofer, Sandra
Kratschmar, Denise V.
Schernthanner, Brigitte
Vuorinen, Anna
Schuster, Daniela
Odermatt, Alex
Easmon, Johnny
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (19) : 5397 - 5400
[9] A mild and general one-pot preparation of cyanoethyl-protected tetrazoles
Kennedy, Lawrence J.
[J]. TETRAHEDRON LETTERS, 2010, 51 (15) : 2010 - 2013
[10] 11β-hydroxysteroid dehydrogenase type 1 deficiency in bone marrow-derived cells reduces atherosclerosis
Kipari, Tiina
Hadoke, Patrick W. F.
Iqbal, Javaid
Man, Tak-Yung
Miller, Eileen
Coutinho, Agnes E.
Zhang, Zhenguang
Sullivan, Katie M.
Mitic, Tijana
Livingstone, Dawn E. W.
Schrecker, Christopher
Samuel, Kay
White, Christopher I.
Bouhlel, M. Amine
Chinetti-Gbaguidi, Giulia
Staels, Bart
Andrew, Ruth
Walker, Brian R.
Savill, John S.
Chapman, Karen E.
Seckl, Jonathan R.
[J]. FASEB JOURNAL, 2013, 27 (04) : 1519 - 1531

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