Second generation of hydroxyethylamine BACE-1 inhibitors: Optimizing potency and oral bioavailability

被引：58

作者：

Charrier, Nicolas ^{[1
]}

Clarke, Brian ^{[1
]}

Cutler, Leanne ^{[1
]}

Demont, Emmanuel ^{[1
]}

Dingwall, Colin ^{[1
]}

Dunsdon, Rachel ^{[1
]}

East, Philip ^{[1
]}

Hawkins, Julie ^{[1
]}

Howes, Colin ^{[1
]}

Hussain, Ishrut ^{[1
]}

Jeffrey, Phil ^{[1
]}

Maile, Graham ^{[1
]}

Matico, Rosalie ^{[1
]}

Mosley, Julie ^{[1
]}

Naylor, Alan ^{[1
]}

O'Brien, Alistair ^{[1
]}

Redshaw, Sally ^{[1
]}

Rowland, Paul ^{[1
]}

Soleil, Virginie ^{[1
]}

Smith, Kathrine J. ^{[1
]}

Sweitzer, Sharon ^{[1
]}

Theobald, Pam ^{[1
]}

Vesey, David ^{[1
]}

Walter, Daryl S. ^{[1
]}

Wayne, Gareth ^{[1
]}

机构：

[1] GlaxoSmithKline Inc, Neurol & Gastrointestinal Ctr Excellence Drug Dis, Harlow CM19 5AW, Essex, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 11期

关键词：

D O I：

10.1021/jm800138h

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

BACE-1 inhibition has the potential to provide a disease-modifying therapy for the treatment of Alzheimer's disease. Optimization of a first generation of BACE-1 inhibitors led to the discovery of novel hydroxyethylamines (HEAs) bearing a tricyclic nonprime side. These derivatives have nanomolar cell potency and are orally bioavailable.

引用

页码：3313 / 3317

页数：5

共 24 条

[1] Role of transport proteins in drug absorption, distribution and excretion [J].

Ayrton, A ;

Morgan, P .

XENOBIOTICA, 2001, 31 (8-9) :469-497

[2] 2-amino-3,4-dihydroquinazolines as inhibitors of BACE-1 (β-site APP cleaving enzyme):: Use of structure based design to convert a micromolar hit into a nanomolar lead [J].

Baxter, Ellen W. ;

Conway, Kelly A. ;

Kennis, Ludo ;

Bischoff, Francois ;

Mercken, Marc H. ;

De Winter, Hans L. ;

Reynolds, Charles H. ;

Tounge, Brett A. ;

Luo, Chi ;

Scott, Malcolm K. ;

Huang, Yifang ;

Braeken, Mirielle ;

Pieters, Sere M. A. ;

Berthelot, Didier J. C. ;

Masure, Stefan ;

Bruinzeel, Wouter D. ;

Jordan, Alfonzo D. ;

Parker, Michael H. ;

Boyd, Robert E. ;

Qu, Junya ;

Alexander, Richard S. ;

Brenneman, Douglas E. ;

Reitz, Allen B. .

JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (18) :4261-4264

[3] BACE-1 inhibitors part 3: Identification of hydroxy ethylamines (HEAs) with nanomolar potency in cells [J].

Beswick, Paul ;

Charrier, Nicolas ;

Clarke, Brian ;

Demont, Emmanuel ;

Dingwall, Colin ;

Dunsdon, Rachel ;

Faller, Andrew ;

Gleave, Robert ;

Hawkins, Julie ;

Hussain, Ishrut ;

Johnson, Christopher N. ;

MacPherson, David ;

Maile, Graham ;

Matico, Rosalie ;

Milner, Peter ;

Mosley, Julie ;

Naylor, Alan ;

O'Brien, Alistair ;

Redshaw, Sally ;

Riddell, David ;

Rowland, Paul ;

Skidmore, John ;

Soleil, Virginie ;

Smith, Kathrine J. ;

Stanway, Steven ;

Stemp, Geoffrey ;

Stuart, Alistair ;

Sweitzer, Sharon ;

Theobald, Pam ;

Vesey, David ;

Walter, Daryl S. ;

Ward, John ;

Wayne, Gareth .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2008, 18 (03) :1022-1026

[4] BACE1 is the major β-secretase for generation of Aβ peptides by neurons [J].

Cai, HB ;

Wang, YS ;

McCarthy, D ;

Wen, HJ ;

Borchelt, DR ;

Price, DL ;

Wong, PC .

NATURE NEUROSCIENCE, 2001, 4 (03) :233-234

[5] Synthesis of indoles: Efficient functionalisation of the 7-position [J].

Charrier, Nicolas ;

Demont, Emmanuel ;

Dunsdon, Rachel ;

Maile, Graham ;

Naylor, Alan ;

O'Brien, Alistair ;

Redshaw, Sally ;

Theobald, Pam ;

Vesey, David ;

Walter, Daryl .

SYNTHESIS-STUTTGART, 2006, (20) :3467-3477

[6] Application of fragment screening by X-ray crystallography to the discovery of aminopyridines as inhibitors of β-secretase [J].

Congreve, Miles ;

Aharony, David ;

Albert, Jeffrey ;

Callaghan, Owen ;

Campbell, James ;

Carr, Robin A. E. ;

Chessari, Gianni ;

Cowan, Suzanna ;

Edwards, Philip D. ;

Frederickson, Martyn ;

McMenamin, Rachel ;

Murray, Christopher W. ;

Patel, Sahil ;

Wallis, Nicola .

JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (06) :1124-1132

[7] Drug therapy - Alzheimer's disease [J].

Cummings, JL .

NEW ENGLAND JOURNAL OF MEDICINE, 2004, 351 (01) :56-67

[8] Classification analysis of P-glycoprotein substrate specificity [J].

Didziapetris, R ;

Japertas, P ;

Avdeef, A ;

Petrauskas, A .

JOURNAL OF DRUG TARGETING, 2003, 11 (07) :391-406

[9]

Durham TB, 2006, CURR OPIN DRUG DISC, V9, P776

[10] Application of fragment-based lead generation to the discovery of novel, cyclic amidine β-secretase inhibitors with nanomolar potency, cellular activity, and high ligand efficiency [J].

Edwards, Philip D. ;

Albert, Jeffrey S. ;

Sylvester, Mark ;

Aharony, David ;

Andisik, Donald ;

Callaghan, Owen ;

Campbell, James B. ;

Carr, Robin A. ;

Chessari, Gianni ;

Congreve, Miles ;

Frederickson, Martyn ;

Folmer, Rutger H. A. ;

Geschwindner, Stefan ;

Koether, Gerard ;

Kolmodin, Karin ;

Krumrine, Jennifer ;

Mauger, Russell C. ;

Murray, Christopher W. ;

Olsson, Lise-Lotte ;

Patel, Sahil ;

Spear, Nate ;

Tian, Gaochao .

JOURNAL OF MEDICINAL CHEMISTRY, 2007, 50 (24) :5912-5925

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