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Preparation of Thieno[3,2‐ h ]cinnolinones as Matrix Metalloproteinase Inhibitors
Author(s) -
Pinna Gérard A.,
Curzu Maria M.,
Murineddu Gabriele,
Chelucci Giorgio,
Cignarella Giorgio,
Menta Ernesto,
Krell Hans W.,
Rastelli Giulio,
Ferrari Anna M.
Publication year - 2000
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/(sici)1521-4184(200002)333:2/3<37::aid-ardp37>3.0.co;2-v
Subject(s) - chemistry , stereochemistry , matrix metalloproteinase , active site , enzyme inhibitor , peptide , matrix metalloproteinase inhibitor , enzyme , binding site , biochemistry
A new series of thieno[3,2‐ h ]cinnolinone analogues was synthesized which is structurally related to 2,3,4,4a,5,6‐hexahydrothieno[3,2‐ h ]cinnolin‐3‐one 1 , a weak inhibitor of the matrix metalloproteinase MMP‐8 (human neutrophil collagenase). Preliminary SAR studies have shown that while C 4a ‐methyl, C 7 ‐acetylamino, C 7 and C 8 ‐nitro substitution, and C 4 ‐C 4a olefination provided no increase in activity relative to 1 , C 8 ‐acetylamino substitution as in 5 and 8 was favourable. Moreover, to predict how the thieno[3,2‐ h ]cinnolinone inhibitors might bind to MMP‐8, the unsubstituted compound 9 was docked into the MMP‐8 crystal structure. These studies revealed that inhibitor 9 does not seem to be able to coordinate the catalytically‐active zinc ion but preferably interact with the peptide‐binding region of the active site.