Discovery of CGS 27023A, a non-peptidic, potent, and orally active stromelysin inhibitor that blocks cartilage degradation in rabbits

被引：316

作者：

MacPherson, LJ

Bayburt, EK

Capparelli, MP

Carroll, BJ

Goldstein, R

Justice, MR

Zhu, LJ

Hu, SI

Melton, RA

Fryer, L

Goldberg, RL

Doughty, JR

Spirito, S

Blancuzzi, V

Wilson, D

OByrne, EM

Ganu, V

Parker, DT

机构：

[1] Research Department, Novartis Pharmaceuticals, Summit, NJ 07901

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1997年 / 40卷 / 16期

关键词：

D O I：

10.1021/jm960871c

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Structure-activity relationships of a lead hydroxamic acid inhibitor of recombinant human stromelysin were systematically defined by taking advantage of a concise synthesis that allowed diverse functionality to be explored at each position in a template. An ex vivo rat model and an in vivo rabbit model of stromelysin-induced cartilage degradation were used to further optimize these analogs for oral activity and duration of action. The culmination of these modifications resulted in CGS 27023A, a potent, orally active stromelysin inhibitor that blocks the erosion of cartilage matrix.

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页码：2525 / 2532

页数：8

相关论文

共 30 条

[11]

GONNELLA NC, UNPUB BIOORG MED CHE

[12] THE NMR STRUCTURE OF THE INHIBITED CATALYTIC DOMAIN OF HUMAN STROMELYSIN-1 [J].

GOOLEY, PR ;

OCONNELL, JF ;

MARCY, AI ;

CUCA, GC ;

SALOWE, SP ;

BUSH, BL ;

HERMES, JD ;

ESSER, CK ;

HAGMANN, WK ;

SPRINGER, JP ;

JOHNSON, BA .

NATURE STRUCTURAL BIOLOGY, 1994, 1 (02) :111-118

[13] INHIBITION OF MATRIX METALLOPROTEINASES BY HYDROXAMATES CONTAINING HETEROATOM-BASED MODIFICATIONS OF THE P-1' GROUP [J].

GOWRAVARAM, MR ;

TOMCZUK, BE ;

JOHNSON, JS ;

DELECKI, D ;

COOK, ER ;

GHOSE, AK ;

MATHIOWETZ, AM ;

SPURLINO, JC ;

RUBIN, B ;

SMITH, DL ;

PULVINO, T ;

WAHL, RC .

JOURNAL OF MEDICINAL CHEMISTRY, 1995, 38 (14) :2570-2581

[14] A SEMICONTINUOUS, HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY-BASED ASSAY FOR STROMELYSIN [J].

HARRISON, R ;

TEAHAN, J ;

STEIN, R .

ANALYTICAL BIOCHEMISTRY, 1989, 180 (01) :110-113

[15] METALLOPROTEINASES, TISSUE INHIBITOR, AND PROTEOGLYCAN FRAGMENTS IN KNEE SYNOVIAL-FLUID IN HUMAN OSTEOARTHRITIS [J].

LOHMANDER, LS ;

HOERRNER, LA ;

LARK, MW .

ARTHRITIS AND RHEUMATISM, 1993, 36 (02) :181-189

[16] PROTEOGLYCANS OF JOINT CARTILAGE - STRUCTURE, FUNCTION, TURNOVER AND ROLE AS MARKERS OF JOINT DISEASE [J].

LOHMANDER, S .

BAILLIERES CLINICAL RHEUMATOLOGY, 1988, 2 (01) :37-62

[17] DESIGN AND SYNTHESIS OF AN ORALLY-ACTIVE MACROCYCLIC NEUTRAL ENDOPEPTIDASE-24.11 INHIBITOR [J].

MACPHERSON, LJ ;

BAYBURT, EK ;

CAPPARELLI, MP ;

BOHACEK, RS ;

CLARKE, FH ;

GHAI, RD ;

SAKANE, Y ;

BERRY, CJ ;

PEPPARD, JV ;

TRAPANI, AJ .

JOURNAL OF MEDICINAL CHEMISTRY, 1993, 36 (24) :3821-3828

[18] Inhibition of matrix metalloproteinases: An examination of the S1' pocket [J].

Miller, A ;

Askew, M ;

Beckett, RP ;

Bellamy, CL ;

Bone, EA ;

Coates, RE ;

Davidson, AH ;

Drummond, AH ;

Huxley, P ;

Martin, FM ;

Saroglou, L ;

Thompson, AJ ;

vanDijk, SE ;

Whittaker, M .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1997, 7 (02) :193-198

[19] STROMELYSIN IS AN ACTIVATOR OF PROCOLLAGENASE - A STUDY WITH NATURAL AND RECOMBINANT ENZYMES [J].

MURPHY, G ;

COCKETT, MI ;

STEPHENS, PE ;

SMITH, BJ ;

DOCHERTY, AJP .

BIOCHEMICAL JOURNAL, 1987, 248 (01) :265-268

[20]

OBRYNE EM, 1995, INFLAMM RES S2, V44, pS117