Design and synthesis of highly active Alzheimer's β-secretase (BACE1) inhibitors, KMI-420 and KMI-429, with enhanced chemical stability

被引：94

作者：

Kimura, T

Shuto, D

Hamada, Y

Igawa, N

Kasai, S

Liu, P

Hidaka, K

Hamada, T

Hayashi, Y

Kiso, Y ^{[1
]}

机构：

[1] Kyoto Pharmaceut Univ, Ctr Frontier Res Med Sci, Dept Med Chem, Yamashima Ku, Kyoto 6078412, Japan

[2] Kyoto Pharmaceut Univ, Century COE Program 21st, Yamashima Ku, Kyoto 6078412, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2005年 / 15卷 / 01期

关键词：

Alzheimer's disease; BACE1; inhibitor; beta-secretase; bioisostere;

D O I：

10.1016/j.bmcl.2004.09.090

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Recently, we reported potent and small-sized BACE1 inhibitors KMI-358 and KMI-370 in which the Glu residue is replaced by a beta-N-oxalyl-DAP (L-alpha,beta-diaminopropionyl) residue at the P-4 position. The beta-N-oxalyl-DAP group is important for enhancing BACE1 inhibitory activity, but these inhibitors isomerized to alpha-N-oxalyl-DAP derivatives in solvents. Hence, we used a tetrazole moiety as a bioisostere of the free carboxylic acid of the oxalyl group. KMI-420 and KMI-429, containing a tetrazole ring, showed improved stability and potent enzyme inhibitory activity. (C) 2004 Elsevier Ltd. All rights reserved.

引用

收藏

页码：211 / 215

页数：5

相关论文

共 30 条

[1] THERMAL-ISOMERIZATION OF N-OXALYL DERIVATIVES OF DIAMINO ACIDS [J].

ABEGAZ, BM ;

NUNN, PB ;

DEBRUYN, A ;

LAMBEIN, F .

PHYTOCHEMISTRY, 1993, 33 (05) :1121-1123

[2] ISOLATION OF ALPHA- AND GAMMA-OXALYL DERIVATIVES OF ALPHA,GAMMA-DIAMINOBUTYRIC ACID FROM SEEDS OF LATHYRUS LATIFOLIUS AND DETECTION OF ALPHA-OXALYL ISOMER OF NEUROTOXIN ALPHA-AMINO-BETA-OXALYL-AMINOPROPIONIC ACID WHICH OCCURS TOGETHER WITH NEUROTOXIN IN THIS AND OTHER SPECIES [J].

BELL, EA ;

ODONOVAN, JP .

PHYTOCHEMISTRY, 1966, 5 (06) :1211-+

[3] Design of potent inhibitors for human brain memapsin 2 (β-secretase) [J].

Ghosh, AK ;

Shin, DW ;

Downs, D ;

Koelsch, G ;

Lin, XL ;

Ermolieff, J ;

Tang, J .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2000, 122 (14) :3522-3523

[4] Structure-based design:: Potent inhibitors of human brain memapsin 2 (β-secretase) [J].

Ghosh, AK ;

Bilcer, G ;

Harwood, C ;

Kawahama, R ;

Shin, D ;

Hussain, KA ;

Hong, L ;

Loy, JA ;

Nguyen, C ;

Koelsch, G ;

Ermolieff, J ;

Tang, J .

JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (18) :2865-2868

[5] Water-soluble prodrugs of dipeptide HIV protease inhibitors based on O→N intramolecular acyl migration:: design, synthesis and kinetic study [J].

Hamada, Y ;

Matsumoto, H ;

Yamaguchi, S ;

Kimura, T ;

Hayashi, Y ;

Kiso, Y .

BIOORGANIC & MEDICINAL CHEMISTRY, 2004, 12 (01) :159-170

[6] Effect of the acyl groups on O→N acyl migration in the water-soluble Prodrugs of HIV-1 protease inhibitor [J].

Hamada, Y ;

Matsumoto, H ;

Kimura, T ;

Hayashi, Y ;

Kiso, Y .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (16) :2727-2730

[7] New water-soluble prodrugs of HIV protease inhibitors based on O→N intramolecular acyl migration [J].

Hamada, Y ;

Ohtake, J ;

Sohma, Y ;

Kimura, T ;

Hayashi, Y ;

Kiso, Y .

BIOORGANIC & MEDICINAL CHEMISTRY, 2002, 10 (12) :4155-4167

[8] Structure of the protease domain of memapsin 2 (β-secretase) complexed with inhibitor [J].

Hong, L ;

Koelsch, G ;

Lin, XL ;

Wu, SL ;

Terzyan, S ;

Ghosh, AK ;

Zhang, XC ;

Tang, J .

SCIENCE, 2000, 290 (5489) :150-153

[9] Identification of a novel aspartic protease (Asp 2) as β-secretase [J].

Hussain, I ;

Powell, D ;

Howlett, DR ;

Tew, DG ;

Week, TD ;

Chapman, C ;

Gloger, IS ;

Murphy, KE ;

Southan, CD ;

Ryan, DM ;

Smith, TS ;

Simmons, DL ;

Walsh, FS ;

Dingwall, C ;

Christie, G .

MOLECULAR AND CELLULAR NEUROSCIENCE, 1999, 14 (06) :419-427

[10] KMI-358 and KMI-370, highly potent and small-sized BACE1 inhibitors containing phenylnorstatine [J].

Kimura, T ;

Shuto, D ;

Kasai, S ;

Liu, P ;

Hidaka, K ;

Hamada, T ;

Hayashi, Y ;

Hattori, C ;

Asai, M ;

Kitazume, S ;

Saido, TC ;

Ishiura, S ;

Kiso, Y .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (06) :1527-1531