Design and synthesis of hydroxyethylene-based peptidomimetic inhibitors of human β-secretase

被引：103

作者：

Hom, RK

Gailunas, AF

Mamo, S

Fang, LY

Tung, JS

Walker, DE

Davis, D

Thorsett, ED

Jewett, NE

Moon, JB

John, V

机构：

[1] Elan, San Francisco, CA 94080 USA

[2] Pfizer Corp, Kalamazoo, MI 49007 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 01期

关键词：

D O I：

10.1021/jm0304008

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The hydroxyethylene (HE) transition state isostere was developed as a scaffold to provide potent, small molecule inhibitors of human beta-secretase (BACE). The previous work on the statine series proved critical to the discovery of HE structure-activity relationships. Compound 20 with the N-terminal isophthalamide proved to be the most potent HE inhibitor (IC50 = 30 nM) toward BACK Unlike the statine series, we identified HE inhibitors without carboxylic acids on the C terminus, leading to enhanced cell penetration and making them attractive candidates for further drug development in Alzheimer's disease.

引用

页码：158 / 164

页数：7

共 22 条

[1] HIGHLY DIASTEREOSELECTIVE ALKYLATIONS OF CHIRAL AMIDE ENOLATES - NEW ROUTES TO HYDROXYETHYLENE DIPEPTIDE ISOSTERE INHIBITORS OF HIV-1 PROTEASE [J].

ASKIN, D ;

WALLACE, MA ;

VACCA, JP ;

REAMER, RA ;

VOLANTE, RP ;

SHINKAI, I .

JOURNAL OF ORGANIC CHEMISTRY, 1992, 57 (10) :2771-2773

[2]

BASHA A, 1977, TETRAHEDRON LETT, P4171

[3] 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

[4] AN INTERNAL COORDINATE MONTE-CARLO METHOD FOR SEARCHING CONFORMATIONAL SPACE [J].

CHANG, G ;

GUIDA, WC ;

STILL, WC .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1989, 111 (12) :4379-4386

[5] Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain [J].

Dovey, HF ;

John, V ;

Anderson, JP ;

Chen, LZ ;

Andrieu, PD ;

Fang, LY ;

Freedman, SB ;

Folmer, B ;

Goldbach, E ;

Holsztynska, EJ ;

Hu, KL ;

Johnson-Wood, KL ;

Kennedy, SL ;

Kholedenko, D ;

Knops, JE ;

Latimer, LH ;

Lee, M ;

Liao, Z ;

Lieberburg, IM ;

Motter, RN ;

Mutter, LC ;

Nietz, J ;

Quinn, KP ;

Sacchi, KL ;

Seubert, PA ;

Shopp, GM ;

Thorsett, ED ;

Tung, JS ;

Wu, J ;

Yang, S ;

Yin, CT ;

Schenk, DB ;

May, PC ;

Altstiel, LD ;

Bender, MH ;

Boggs, LN ;

Britton, TC ;

Clemens, JC ;

Czilli, DL ;

Dieckman-McGinty, DK ;

Droste, JJ ;

Fuson, KS ;

Gitter, BD ;

Hyslop, PA ;

Johnstone, EM ;

Li, WY ;

Little, SP ;

Mabry, TE ;

Miller, FD ;

Ni, B .

JOURNAL OF NEUROCHEMISTRY, 2001, 76 (01) :173-181

[6] Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 3. Structure - Activity studies of ketomethylene-containing peptidomimetics [J].

Dragovich, PS ;

Prins, TJ ;

Zhou, R ;

Fuhrman, SA ;

Patick, AK ;

Matthews, DA ;

Ford, CE ;

Meador, JW ;

Ferre, RA ;

Worland, ST .

JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (07) :1203-1212

[7] 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

[8] Mimetics of the Peptide β-Strand [J].

Glenn, Matthew P. ;

Fairlie, David P. .

MINI-REVIEWS IN MEDICINAL CHEMISTRY, 2002, 2 (05) :433-445

[9] RENIN INHIBITORS [J].

GREENLEE, WJ .

MEDICINAL RESEARCH REVIEWS, 1990, 10 (02) :173-236

[10] Design and synthesis of statine-based cell-permeable peptidomimetic inhibitors of human β-secretase [J].

Hom, RK ;

Fang, LY ;

Mamo, S ;

Tung, JS ;

Guinn, AC ;

Walker, DE ;

Davis, DL ;

Gailunas, AF ;

Thorsett, ED ;

Sinha, S ;

Knops, JE ;

Jewett, NE ;

Anderson, JP ;

John, V .

JOURNAL OF MEDICINAL CHEMISTRY, 2003, 46 (10) :1799-1802

← 1 2 3 →