Synthesis of potent β-secretase inhibitors containing a hydroxyethylamine dipeptide isostere and their structure-activity relationship studies

被引：68

作者：

Tamamura, H ^{[1
]}

Kato, T ^{[1
]}

Otaka, A ^{[1
]}

Fujii, N ^{[1
]}

机构：

[1] Kyoto Univ, Grad Sch Pharmaceut Sci, Sakyo Ku, Kyoto 6068501, Japan

来源：

ORGANIC & BIOMOLECULAR CHEMISTRY | 2003年 / 1卷 / 14期

关键词：

D O I：

10.1039/b304842j

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

Several beta-secretase inhibitors were designed based on hydroxyethylamine dipeptide isostere (HDI) structures and were synthesized by a methodology using the aza-Payne rearragement and O,N-acyl transfer reactions to study their structure-activity relationships. Among these pseudopeptides, effective compounds were developed as the first beta-secretase inhibitors containing the HDI transition state mimic with potent enzyme inhibitory activity (IC50 < 100 nM).

引用

页码：2468 / 2473

页数：6

共 33 条

[1] Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere [J].

Ghosh, AK ;

Kincaid, JF ;

Cho, WH ;

Walters, DE ;

Krishnan, K ;

Hussain, KA ;

Koo, Y ;

Cho, H ;

Rudall, C ;

Holland, L ;

Buthod, J .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1998, 8 (06) :687-690

[2] 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

[3] 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

[4]

HOM RK, IN PRESS J MED CHEM

[5] 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

[6] Crystal structure of memapsin 2 (β-secretase) in complex with an inhibitor OM00-3 [J].

Hong, L ;

Turner, RT ;

Koelsch, G ;

Shin, DG ;

Ghosh, AK ;

Tang, J .

BIOCHEMISTRY, 2002, 41 (36) :10963-10967

[7] ORALLY ACTIVE WATER-SOLUBLE N,O-ACYL TRANSFER PRODUCTS OF A BETA,GAMMA-BISHYDROXYL AMIDE CONTAINING RENIN INHIBITOR [J].

HURLEY, TR ;

COLSON, CE ;

HICKS, G ;

RYAN, MJ .

JOURNAL OF MEDICINAL CHEMISTRY, 1993, 36 (10) :1496-1498

[8] 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

[9] AZA-PAYNE REARRANGEMENT OF ACTIVATED 2-AZIRIDINEMETHANOLS AND 2,3-EPOXY AMINES UNDER BASIC CONDITIONS [J].

IBUKA, T ;

NAKAI, K ;

HABASHITA, H ;

HOTTA, Y ;

TAMAMURA, H ;

FUJII, N ;

MIMURA, N ;

MIWA, Y ;

TAGA, T ;

CHOUNAN, Y ;

YAMAMOTO, Y ;

OTAKA, A .

JOURNAL OF ORGANIC CHEMISTRY, 1995, 60 (07) :2044-2058

[10] Viracept (nelfinavir mesylate, AG1343): A potent, orally bioavailable inhibitor of HIV-1 protease [J].

Kaldor, SW ;

Kalish, VJ ;

Davies, JF ;

Shetty, BV ;

Fritz, JE ;

Appelt, K ;

Burgess, JA ;

Campanale, KM ;

Chirgadze, NY ;

Clawson, DK ;

Dressman, BA ;

Hatch, SD ;

Khalil, DA ;

Kosa, MB ;

Lubbehusen, PP ;

Muesing, MA ;

Patick, AK ;

Reich, SH ;

Su, KS ;

Tatlock, JH .

JOURNAL OF MEDICINAL CHEMISTRY, 1997, 40 (24) :3979-3985

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