A novel series of highly selective inhibitors of MMP-3.
The design and synthesis of a series of highly selective hydroxamate inhibitors of stromelysin-1 (MMP-3) is described. Substitution of a 4-biaryl piperidine sulfonamide core, which binds at the S1' subsite of MMP-3, was optimised to give potent inhibitors of MMP-3, with greater than 300-fold selectivity over MMP-1, MMP-2, MMP-9 and MMP-14. Compounds 26 and 27 were identified as having the best balance of pharmacology and properties required for topical drug delivery.
Whitlock
Gavin A
GA
Sandwich Chemistry Department, Pfizer Global Research and Development, Sandwich Labs, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. gavin.whitlock@pfizer.com
Dack
Kevin N
KN
Dickinson
Roger P
RP
Lewis
Mark L
ML
D000596:Amino Acids / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D016503:Drug Delivery Systems; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000596:Amino Acids; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013449:Sulfonamides