Sulfonamide-based acyclic and conformationally constrained MMP inhibitors: from computer-assisted design to nanomolar compounds.
The present account relates to our studies in the computer assisted design and synthesis of acyclic and cyclic MMP inhibitors. Our early efforts focused on the preparation of cyclopropane and tetrahydrofuran-based mimics of batimastat which were not active. The discovery of subnanomolar sulfonamide-based acyclic inhibitors instigated the design of novel target compounds. Thus, with the help of a fully automated and reliable docking program, we embarked on the design and synthesis of enantiopure inhibitors incorporating cyclic scaffolds. This ultimately led to compounds exhibiting inhibitory activities in the nanomolar range. Interestingly, the qualitative ranking prediction was found to be in good agreement with the observed activities.
Department of Chemistry, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Québec H3C 3J7, Canada. stephen.hanessian@umontreal.ca
Stephen
S
Hanessian
Nicolas
N
Moitessier
D000818:Animals; D017076:Computer-Aided Design; D015195:Drug Design; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013449:Sulfonamides