Stereospecific synthesis of 5-substituted 2-bisarylthiocyclopentane carboxylic acids as specific matrix metalloproteinase inhibitors.
The synthesis and structure-activity relationship (SAR) studies of a series of cyclopentane carboxylic acid matrix metalloproteinase (MMP) inhibitors are described. Potent and specific MMP-2, -3, -9, -13 inhibitors were obtained by regio- and stereoselective substitutions at positions 2 and 5 on the cyclopentane ring. Compounds 2a and 2e are active in the mouse B16-F10 metastasis model and display very good pharmacokinetic parameters.
Le Diguarher
Thierry
T
Institut de Recherches Servier, 125 chemin de Ronde, 78290 Croissy sur Seine, France, and Technologie Servier, 25-27 rue E. Vignat, 45007 Orléans, France.
Chollet
Anne-Marie
AM
Bertrand
Marc
M
Hennig
Philippe
P
Raimbaud
Eric
E
Sabatini
Massimo
M
Guilbaud
Nicolas
N
Pierré
Alain
A
Tucker
Gordon C
GC
Casara
Patrick
P
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D018938:Caco-2 Cells; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000737:chemistry; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D009362:Neoplasm Metastasis; D010539:Permeability; D010797:Phthalimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C477194:2-(2-(4'-chlorobiphenylthio))-5-(2-(4-oxo-4H-benzo(d)(1,2,3)triazin-3-ylmethyl))cyclopentanecarboxylic acid; C477195:2-(2-(4'-fluorobiphenyl)ethylthio)-5-(phthalimidomethyl)cyclopentanecarboxylic acid; D000970:Antineoplastic Agents; D003517:Cyclopentanes; D061965:Matrix Metalloproteinase Inhibitors; D010797:Phthalimides; D011480:Protease Inhibitors; D014227:Triazines; D020782:Matrix Metalloproteinases