RÉSUMÉ
Seeking compounds preferentially potent and selective for MMP-13, we reported in the preceding Letter on a series of hydroxamic acids with a flexible benzamide tail groups.(1a) Here, we replace the amide moiety with non-hydrolyzable heterocycles in an effort to improve half-life. We identify a hydroxamate tetrazole 4e that spares MMP-1 and -14, shows >400-fold selectivity versus MMP-8 and >600-fold selectivity versus MMP-2, and has a 4.8 h half-life in rats. X-ray data (1.9 Å) for tetrazole 4c is presented.
Sujet(s)
Amides/synthèse chimique , Antienzymes/synthèse chimique , Composés hétérocycliques/synthèse chimique , Acides hydroxamiques/synthèse chimique , Inhibiteurs de métalloprotéinases matricielles , Sulfones/synthèse chimique , Amides/composition chimique , Animaux , Cristallographie aux rayons X , Antienzymes/composition chimique , Composés hétérocycliques/composition chimique , Acides hydroxamiques/composition chimique , Matrix Metalloproteinase 13/composition chimique , Modèles moléculaires , Rats , Relation structure-activité , Spécificité du substrat , Sulfones/composition chimiqueRÉSUMÉ
α-Sulfone-α-piperidine and α-tetrahydropyranyl hydroxamates were explored that are potent inhibitors of MMP's-2, -9, and -13 that spare MMP-1, with oral efficacy in inhibiting tumor growth in mice and left-ventricular hypertrophy in rats and in the bovine cartilage degradation ex vivo explant system. α-Piperidine 19v (SC-78080/SD-2590) was selected for development toward the initial indication of cancer, while α-piperidine and α-tetrahydropyranyl hydroxamates 19w (SC-77964) and 9i (SC-77774), respectively, were identified as backup compounds.
Sujet(s)
Anti-inflammatoires/synthèse chimique , Antinéoplasiques/synthèse chimique , Agents cardiovasculaires/synthèse chimique , Acides hydroxamiques/synthèse chimique , Inhibiteurs de métalloprotéinases matricielles , Pipéridines/synthèse chimique , Pyrannes/synthèse chimique , Sulfones/synthèse chimique , Animaux , Anti-inflammatoires/composition chimique , Anti-inflammatoires/pharmacologie , Antinéoplasiques/composition chimique , Antinéoplasiques/pharmacologie , Biodisponibilité , Agents cardiovasculaires/composition chimique , Agents cardiovasculaires/pharmacologie , Cartilage articulaire/effets des médicaments et des substances chimiques , Cartilage articulaire/anatomopathologie , Bovins , Cristallographie aux rayons X , Humains , Acides hydroxamiques/composition chimique , Acides hydroxamiques/pharmacologie , Hypertrophie ventriculaire gauche/traitement médicamenteux , Macaca fascicularis , Souris , Souris nude , Modèles moléculaires , Structure moléculaire , Pipéridines/composition chimique , Pipéridines/pharmacologie , Pyrannes/composition chimique , Pyrannes/pharmacologie , Rats , Relation structure-activité , Sulfones/composition chimique , Sulfones/pharmacologie , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
Osteoarthritis is characterized by the loss of aggrecan and collagen from the cartilage extracellular matrix. The proteinases responsible for the breakdown of cartilage aggrecan include ADAMTS-4 (aggrecanase 1) and ADAMTS-5 (aggrecanase 2). Post-translational inhibition of ADAMTS-4/-5 activity may be important for maintaining normal homeostasis of aggrecan metabolism, and thus, any disruption to this inhibition could lead to accelerated aggrecan breakdown. To date TIMP-3 (tissue inhibitor of matrix metalloproteinases-3) is the only endogenous inhibitor of ADAMTS-4/-5 that has been identified. In the present studies we identify alpha(2)-macroglobulin (alpha(2)M) as an additional endogenous inhibitor of ADAMTS-4 and ADAMTS-5. alpha(2)M inhibited the activity of both ADAMTS-4 and ADAMTS-5 in a concentration-dependent manner, demonstrating 1:1 stoichiometry with second-order rate constants on the order of 10(6) and 10(5) m(-1) s(-1), respectively. Inhibition of the aggrecanases was mediated by proteolysis of the bait region within alpha(2)M, resulting in physical entrapment of these proteinases. Both ADAMTS-4 and ADAMTS-5 cleaved alpha(2)M at Met(690)/Gly(691), representing a novel proteinase cleavage site within alpha(2)M and a novel site of cleavage for ADAMTS-4 and ADAMTS-5. Finally, the use of the anti-neoepitope antibodies to detect aggrecanase-generated alpha(2)M-fragments in synovial fluid was investigated and found to be uninformative.