Repurposing human PDE4 inhibitors for neglected tropical diseases: Design, synthesis and evaluation of cilomilast analogues as Trypanosoma brucei PDEB1 inhibitors

被引：23

作者：

Amata, Emanuele ^{[1
]}

Bland, Nicholas D. ^{[2
]}

Hoyt, Charles T. ^{[1
]}

Settimo, Luca ^{[1
]}

Campbell, Robert K. ^{[2
]}

Pollastri, Michael P. ^{[1
]}

机构：

[1] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA

[2] Marine Biol Lab, Josephine Bay Paul Ctr Comparat Mol Biol & Evolut, Woods Hole, MA 02543 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 17期

基金：

美国国家卫生研究院;

关键词：

Antiprotozoal agents; Cilomilast; Phosphodiesterase inhibitors; TbrPDEB1 Trypanosoma brucei; PHARMACOLOGICAL VALIDATION; PHOSPHODIESTERASE B1; SLEEPING SICKNESS; TBRPDEB1; TARGETS; POTENT;

D O I：

10.1016/j.bmcl.2014.07.063

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A medicinal chemistry exploration of the human phosphodiesterase 4 (hPDE4) inhibitor cilomilast (1) was undertaken in order to identify inhibitors of phosphodiesterase B1 of Trypanosoma brucei (TbrPDEB1). T. brucei is the parasite which causes African sleeping sickness, a neglected tropical disease that affects thousands each year, and TbrPDEB1 has been shown to be an essential target of therapeutic relevance. Noting that 1 is a weak inhibitor of TbrPDEB1, we report the design and synthesis of analogs of this compound, culminating in 12b, a sub-micromolar inhibitor of TbrPDEB1 that shows modest inhibition of T. brucei proliferation. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：4084 / 4089

页数：6

共 18 条

[1] Pharmacological Validation of Trypanosoma brucei Phosphodiesterases B1 and B2 as Druggable Targets for African Sleeping Sickness [J].

Bland, Nicholas D. ;

Wang, Cuihua ;

Tallman, Craig ;

Gustafson, Alden E. ;

Wang, Zhouxi ;

Ashton, Trent D. ;

Ochiana, Stefan O. ;

McAllister, Gregory ;

Cotter, Kristina ;

Fang, Anna P. ;

Gechijian, Lara ;

Garceau, Norman ;

Gangurde, Rajiv ;

Ortenberg, Ron ;

Ondrechen, Mary Jo ;

Campbell, Robert K. ;

Pollastri, Michael P. .

JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (23) :8188-8194

[2] Structural basis for the activity of drugs that inhibit phosphodiesterases [J].

Card, GL ;

England, BP ;

Suzuki, Y ;

Fong, D ;

Powell, B ;

Lee, B ;

Luu, C ;

Tabrizizad, M ;

Gillette, S ;

Ibrahim, PN ;

Artis, DR ;

Bollag, G ;

Milburn, MV ;

Kim, SH ;

Schlessinger, J ;

Zhang, KYJ .

STRUCTURE, 2004, 12 (12) :2233-2247

[3] 1,4-cyclohexanecarboxylates: Potent and selective inhibitors of phosphodiesterase 4 for the treatment of asthma [J].

Christensen, SB ;

Guider, A ;

Forster, CJ ;

Gleason, JG ;

Bender, PE ;

Karpinski, JM ;

DeWolf, WE ;

Barnette, MS ;

Underwood, DC ;

Griswold, DE ;

Cieslinski, LB ;

Burman, M ;

Bochnowicz, S ;

Osborn, RR ;

Manning, CD ;

Grous, M ;

Hillegas, LM ;

Bartus, JO ;

Ryan, MD ;

Eggleston, DS ;

Haltiwanger, RC ;

Torphy, TJ .

JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (06) :821-835

[4] Pharmacological Validation of Trypanosoma brucei Phosphodiesterases as Novel Drug Targets [J].

de Koning, Harry P. ;

Gould, Matthew K. ;

Sterk, Geert Jan ;

Tenor, Hermann ;

Kunz, Stefan ;

Luginbuehl, Edith ;

Seebeck, Thomas .

JOURNAL OF INFECTIOUS DISEASES, 2012, 206 (02) :229-237

[5] SAR of a series of 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-α]pyridines as potent inhibitors of human eosinophil phosphodiesterase [J].

Duplantier, Allen J. ;

Bachert, Elizabeth L. ;

Cheng, John B. ;

Cohan, Victoria L. ;

Jenkinson, Teresa H. ;

Kraus, Kenneth G. ;

McKechney, Michael W. ;

Pillar, Joann D. ;

Watson, John W. .

JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (02) :344-349

[6] In silico search for multi-target anti-inflammatories in Chinese herbs and formulas [J].

Ehrman, Thomas M. ;

Barlow, David J. ;

Hylands, Peter J. .

BIOORGANIC & MEDICINAL CHEMISTRY, 2010, 18 (06) :2204-2218

[7] Generation of a set of simple, interpretable ADMET rules of thumb [J].

Gleeson, M. Paul .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (04) :817-834

[8] The preclinical pharmacology of roflumilast - A selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease [J].

Hatzelmann, Armin ;

Morcillo, Esteban J. ;

Lungarella, Giuseppe ;

Adnot, Serge ;

Sanjar, Shahin ;

Beume, Rolf ;

Schudt, Christian ;

Tenor, Hermann .

PULMONARY PHARMACOLOGY & THERAPEUTICS, 2010, 23 (04) :235-256

[9] Discovery of Novel Trypanosoma brucei Phosphodiesterase B1 Inhibitors by Virtual Screening against the Unliganded TbrPDEB1 Crystal Structure [J].

Jansen, Chimed ;

Wang, Huanchen ;

Kooistra, Albert J. ;

de Graaf, Chris ;

Orrling, Kristina M. ;

Tenor, Hermann ;

Seebeck, Thomas ;

Bailey, David ;

de Esch, Iwan J. P. ;

Ke, Hengming ;

Leurs, Rob .

JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (05) :2087-2096

[10] The Trypanosoma brucei cAMP phosphodiesterases TbrPDEB1 and TbrPDEB2:: flagellar enzymes that are essential for parasite virulence [J].

Oberholzer, Michael ;

Marti, Gabriela ;

Baresic, Mario ;

Kunz, Stefan ;

Hemphill, Andrew ;

Seebeck, Thomas .

FASEB JOURNAL, 2007, 21 (03) :720-731

← 1 2 →