Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 2: α-Branched quaternary amines

被引：14

作者：

Hunt, Thomas ^{[1
]}

Atherton-Watson, Hazel C. ^{[1
]}

Collingwood, Stephen P.

Coote, Kevin J. ^{[1
]}

Czarnecki, Sarah ^{[1
]}

Danahay, Henry ^{[1
]}

Howsham, Catherine

Hunt, Peter

Paisley, Derek ^{[1
]}

Young, Alice ^{[1
]}

机构：

[1] Novartis Inst Biomed Res, Resp Dis Area, Horsham RH12 5AB, W Sussex, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 08期

关键词：

ENaC blocker; Epithelial sodium channel; Quaternary amine; Cystic fibrosis; Amiloride; FIBROSIS LUNG-DISEASE; EPITHELIAL NA+ CHANNEL; CYSTIC-FIBROSIS;

D O I：

10.1016/j.bmcl.2012.02.067

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report the synthesis and biological evaluation of a series of novel alpha-branched pyrazinoyl quaternary amines for their ability to block ion transport via the epithelial sodium channel (ENaC) in human bronchial epithelial cells (HBECs). Compound 12g has an IC50 of 30 nM and is highly efficacious in the Guinea-pig tracheal potential difference (TPD) model of ENaC blockade with an ED50 of 1 mu g kg(-1) at 1 h. In addition the SAR results demonstrate for the first time the chiral nature of the binding site of human ENaC. As such, pyrazinoyl quaternary amines represent a promising new class of ENaC blockers for the treatment of cystic fibrosis that are structurally distinct from the pyrazinoyl guanidine chemotype found in prototypical ENaC blockers such as amiloride. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：2877 / 2879

页数：3

共 16 条

[1] ACUTE AND LONG-TERM AMILORIDE INHALATION IN CYSTIC-FIBROSIS LUNG-DISEASE - A RATIONAL APPROACH TO CYSTIC-FIBROSIS THERAPY [J].

APP, EM ;

KING, M ;

HELFESRIEDER, R ;

KOHLER, D ;

MATTHYS, H .

AMERICAN REVIEW OF RESPIRATORY DISEASE, 1990, 141 (03) :605-612

[2] Evidence for airway surface dehydration as the initiating event in CF airway disease [J].

Boucher, R. C. .

JOURNAL OF INTERNAL MEDICINE, 2007, 261 (01) :5-16

[3] Front-runners for pharmacotherapeutic correction of the airway ion transport defect in cystic fibrosis [J].

Clunes, Mark T. ;

Boucher, Richard C. .

CURRENT OPINION IN PHARMACOLOGY, 2008, 8 (03) :292-299

[4]

Collingwood S. P., 2009, International Patent, Patent No. [WO 150 137 A2, 150137]

[5] The guinea-pig tracheal potential difference as an in vivo model for the study of epithelial sodium channel function in the airways [J].

Coote, K. J. ;

Atherton, H. ;

Young, A. ;

Sugar, R. ;

Burrows, R. ;

Smith, N. J. ;

Schlaeppi, J-M ;

Groot-Kormelink, P. J. ;

Gosling, M. ;

Danahay, H. .

BRITISH JOURNAL OF PHARMACOLOGY, 2008, 155 (07) :1025-1033

[6] THE SYNTHESIS OF ALPHA-AMINO-GAMMA-(PARA-HYDROXYPHENYL)BUTYRIC ACID, A HOMOLOGUE OF TYROSINE [J].

EVANS, WC ;

WALKER, N .

JOURNAL OF THE CHEMICAL SOCIETY, 1947, (NOV) :1571-1573

[7] Pharmacological properties of N-(3,5-diamino-6-chloropyrazine-2-carbonyl)-N′-4-[4-(2,3-dihydroxypropoxy)phenyl]butyl-guanidine methanesulfonate (552-02), a novel epithelial sodium channel blocker with potential clinical efficacy for cystic fibrosis lung disease [J].

Hirsh, Andrew J. ;

Zhang, Jim ;

Zamurs, Andra ;

Fleegle, Jacquelyn ;

Thelin, William R. ;

Caldwell, Ray A. ;

Sabater, Juan R. ;

Abraham, William M. ;

Donowitz, Mark ;

Cha, Boyoung ;

Johnson, Kevin B. ;

St George, Judith A. ;

Johnson, M. Ross ;

Boucher, Richard C. .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2008, 325 (01) :77-88

[8] Aerosolized amiloride: Dose effect on nasal bioelectric properties, pharmacokinetics, and effect on sputum expectoration in patients with cystic fibrosis [J].

Hofmann, T ;

Senier, I ;

Bittner, P ;

Huls, G ;

Schwandt, HJ ;

Lindemann, H .

JOURNAL OF AEROSOL MEDICINE-DEPOSITION CLEARANCE AND EFFECTS IN THE LUNG, 1996, 10 (02) :147-158

[9] Discovery of a novel chemotype of potent human ENaC blockers using a bioisostere approach. Part 1: Quaternary amines [J].

Hunt, Thomas ;

Atherton-Watson, Hazel C. ;

Axford, Jake ;

Collingwood, Stephen P. ;

Coote, Kevin J. ;

Cox, Brian ;

Czarnecki, Sarah ;

Danahay, Henry ;

Devereux, Nick ;

Howsham, Catherine ;

Hunt, Peter ;

Paddock, Victoria ;

Paisley, Derek ;

Young, Alice .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (02) :929-932

[10] Structure of acid-sensing ion channel 1 at 1.9A resolution and low pH [J].

Jasti, Jayasankar ;

Furukawa, Hiroyasu ;

Gonzales, Eric B. ;

Gouaux, Eric .

NATURE, 2007, 449 (7160) :316-+

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