Novel Roflumilast analogs as soft PDE4 inhibitors

被引：32

作者：

Boland, Sandro ^{[1
]}

Alen, Jo ^{[1
]}

Bourin, Arnaud ^{[1
]}

Castermans, Karolien ^{[1
]}

Boumans, Nicki ^{[1
]}

Panitti, Laura ^{[1
]}

Vanormelingen, Jessica ^{[1
]}

Leysen, Dirk ^{[1
]}

Defert, Olivier ^{[1
]}

机构：

[1] Amakem NV, B-3590 Diepenbeek, Belgium

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 18期

关键词：

PDE4; inhibitors; Soft drug; SAR; Esterase; COPD; PHOSPHODIESTERASE-4; INHIBITORS; ASTHMA;

D O I：

10.1016/j.bmcl.2014.07.016

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

PDE4 inhibitors are of high interest for treatment of a wide range of inflammatory or autoimmune diseases. Their potential however has not yet been realized due to target-associated side effects, resulting in a low therapeutic window. We herein report the design, synthesis and evaluation of novel PDE4 inhibitors containing a gamma-lactone structure. Such molecules are designed to undergo metabolic inactivation when entering circulation, thereby limiting systemic exposure and reducing the risk for side effects. The resulting inhibitors were highly active on both PDE4B1 and PDE4D2 and underwent rapid degradation in human plasma by paraoxonase 1. In contrast, their metabolites displayed markedly reduced permeability and/or on-target activity. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：4594 / 4597

页数：4

共 26 条

[21] Soto FJ, 2005, CURR OPIN PULM MED, V11, P129
[22] Immunosuppressive and anti-inflammatory effects of cyclic AMP phosphodiesterase (PDE) type 4 inhibitors
Souness, JE
Aldous, D
Sargent, C
[J]. IMMUNOPHARMACOLOGY, 2000, 47 (2-3): : 127 - 162
[23] Roflumilast: the new orally active, selective phophodiesterase-4 inhibitor, for the treatment of COPD
Tashkin, Donald P.
[J]. EXPERT OPINION ON PHARMACOTHERAPY, 2014, 15 (01) : 85 - 96
[24] Ariflo™ (SB 207499), a second generation phosphodiesterase 4 inhibitor for the treatment of asthma and COPD:: from concept to clinic
Torphy, TJ
Barnette, MS
Underwood, DC
Griswold, DE
Christensen, SB
Murdoch, RD
Nieman, RB
Compton, CH
[J]. PULMONARY PHARMACOLOGY & THERAPEUTICS, 1999, 12 (02) : 131 - 135
[25] Quinolines as a novel structural class of potent and selective PDE4 inhibitors. Optimisation for inhaled administration
Woodrow, Michael D.
Ballantine, Stuart P.
Barker, Michael D.
Clarke, Beth J.
Dawson, John
Dean, Tony W.
Delves, Christopher J.
Evans, Brian
Gough, Sharon L.
Guntrip, Steven B.
Holman, Stuart
Holmes, Duncan S.
Kranz, Michael
Lindvaal, Mika K.
Lucas, Fiona S.
Neu, Margarete
Ranshaw, Lisa E.
Solanke, Yemisi E.
Somers, Don O.
Ward, Peter
Wiseman, Joanne O.
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (17) : 5261 - 5265
[26] Design and synthesis of boron-containing PDE4 inhibitors using soft-drug strategy for potential dermatologic anti-inflammatory application
Zhang, Yong-Kang
Plattner, Jacob J.
Akama, Tsutomu
Baker, Stephen J.
Hernandez, Vincent S.
Sanders, Virginia
Freund, Yvonne
Kimura, Richard
Bu, Wei
Hold, Karin M.
Lu, Xiao-Song
[J]. BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (07) : 2270 - 2274

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