title: In silico scaffold evaluation and solid phase approach to identify new gelatinase inhibitors.
abstract: Among matrix metalloproteinases (MMPs), gelatinases MMP-2 (gelatinase A) and MMP-9 (gelatinase B) play a key role in a number of physiological processes such as tissue repair and fibrosis. Many evidences point out their involvement in a series of pathological events, such as arthritis, multiple sclerosis, cardiovascular diseases, inflammatory processes and tumor progression by degradation of the extracellular matrix. To date, the identification of non-specific MMP inhibitors has made difficult the selective targeting of gelatinases. In this work we report the identification, design and synthesis of new gelatinase inhibitors with appropriate drug-like properties and good profile in terms of affinity and selectivity. By a detailed in silico protocol and innovative and versatile solid phase approaches, a series of 4-thiazolydinyl-N-hydroxycarboxyamide derivatives were identified. In particular, compounds 9a and 10a showed a potent inhibitory activity against gelatinase B and good selectivity over the other MMP considered in this study. The identified compounds could represent novel potential candidates as therapeutic agents.
authors.affiliation: Colosseum Combinatorial Chemistry Centre for Technology (C4T SCarl), Via della Ricerca Scientifica snc, I-00133 Rome, Italy. alessandra.topai@uniroma2.it
authors.forename: Alessandra
authors.initials: A
authors.lastname: Topai
authors.forename: Perla
authors.initials: P
authors.lastname: Breccia
authors.forename: Franco
authors.initials: F
authors.lastname: Minissi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Padova
authors.forename: Stefano
authors.initials: S
authors.lastname: Marini
authors.forename: Ilaria
authors.initials: I
authors.lastname: Cerbara
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry; D001665:Binding Sites; D016208:Databases, Factual; D018093:Gelatinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D060327:Solid-Phase Synthesis Techniques; D053778:Thiazolidines / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: C573387:4-thiazolydinyl-N-hydroxycarboxyamide; D000577:Amides; D011480:Protease Inhibitors; D053778:Thiazolidines; D018093:Gelatinases; D020778:Matrix Metalloproteinase 2