Design, synthesis, and biological evaluation of matrix metalloproteinase inhibitors derived from a modified proline scaffold

被引:52
作者
Cheng, MY
De, B
Almstead, NG
Pikul, S
Dowty, ME
Dietsch, CR
Dunaway, CM
Gu, F
Hsieh, LC
Janusz, MJ
Taiwo, YO
Natchus, MG
Hudlicky, T
Mandel, M
机构
[1] Procter & Gamble Co, Mason, OH 45040 USA
[2] Univ Florida, Dept Chem, Gainesville, FL 32611 USA
关键词
D O I
10.1021/jm9904699
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The synthesis and structure-activity relationship (SAR) studies of a series of proline-based matrix metalloproteinase inhibitors are described. The data reveal a remarkable potency enhancement in those compounds that contain an sp(2) center at the C-4 carbon of the ring relative to similar, saturated compounds. This effect was noted in compounds that contained a functionalized oxime moiety or an exomethylene at C-4, and the potencies were typically <10 nM for MMP-3 and <100 nM for MMP-1. Comparisons were then made against compounds with similar functionality where the C-4 carbon was reduced to sp(3) hybridization and the effect was typically an order of magnitude loss in potency. A comparison of compounds 14 and 34 exemplifies this observation. An X-ray structure was obtained for a stromelysin-inhibitor complex which provided insights into the SAR and selectivity trends observed within the series. In vitro intestinal permeability data for many compounds was also accumulated.
引用
收藏
页码:5426 / 5436
页数:11
相关论文
共 41 条
[1]   Expression of matrix metalloproteinase 9 (96-kd gelatinase B) in human rheumatoid arthritis [J].
Ahrens, D ;
Koch, AE ;
Pope, RM ;
SteinPicarella, M ;
Niedbala, MJ .
ARTHRITIS AND RHEUMATISM, 1996, 39 (09) :1576-1587
[2]  
ALMSTEAD NA, 1999, IN PRESS SYNTHESIS B
[3]   Molecular recognition of protein-ligand complexes: Applications to drug design [J].
Babine, RE ;
Bender, SL .
CHEMICAL REVIEWS, 1997, 97 (05) :1359-1472
[4]   Matrix metalloproteinase inhibitors 1998 [J].
Beckett, RP ;
Whittaker, M .
EXPERT OPINION ON THERAPEUTIC PATENTS, 1998, 8 (03) :259-282
[5]   Determination of metalloproteinases, plasminogen-activators and their inhibitors in the synovial fluids of patients with rheumatoid arthritis during chemical synoviorthesis [J].
Blaser, J ;
Triebel, S ;
Maasjosthusmann, U ;
Romisch, J ;
KrahlMateblowski, U ;
Freudenberg, W ;
Fricke, R ;
Tschesche, H .
CLINICA CHIMICA ACTA, 1996, 244 (01) :17-33
[6]   Insights into MMP-TIMP interactions [J].
Bode, W ;
Fernandez-Catalan, C ;
Grams, F ;
Gomis-Rüth, FX ;
Nagase, H ;
Tschesche, H ;
Maskos, K .
INHIBITION OF MATRIX METALLOPROTEINASES: THERAPEUTIC APPLICATIONS, 1999, 878 :73-91
[7]   Matrix metalloproteinases in gastrointestinal cancer [J].
Brown, PD .
GUT, 1998, 43 (02) :161-163
[8]  
Buisson AC, 1996, LAB INVEST, V74, P658
[9]   SILICON-CONTAINING CARBANIONS .2. KETENE THIOACETAL SYNTHESIS VIA 2-LITHIO-2-TRIMETHYLSILYL-1,3-DITHIANE [J].
CAREY, FA ;
COURT, AS .
JOURNAL OF ORGANIC CHEMISTRY, 1972, 37 (12) :1926-&
[10]   Metalloproteinase inhibitors and the prevention of connective tissue breakdown [J].
Cawston, TE .
PHARMACOLOGY & THERAPEUTICS, 1996, 70 (03) :163-182