title: Identification of highly selective inhibitors of collagenase-1 from combinatorial libraries of diketopiperazines.
abstract: Thiol-containing diketopiperazines have been recently identified as novel heterocyclic inhibitors of matrix metalloproteinase (MMPs). The compounds described had similar activities against the MMPs collagenase-1 and gelatinase-B. An inhibitor that showed greater than 10-fold selectivity for collagenase-1 over gelatinase-B was desired. Previously published work with peptidyl hydroxamates and thiols indicated that while preparing gelatinase selective inhibitors was straightforward, there was not an obvious route to selective inhibitors of collagenase-1. Combinatorial libraries were prepared and evaluated for their ability to inhibit collagenase-1 and gelatinase-B substrate hydrolysis. A method for estimating the IC50 values of compounds generated by high-throughput parallel synthesis aided in the identification of compounds with the desired properties. We have found that thiol diketopiperazines derived from nitrophenylalanine are both potent and selective inhibitors of collagenase-1. In addition, we have demonstrated that combinatorial chemistry can be utilized to identify molecules with a desired selectivity profile without access to the traditional tools of rational drug design.
authors.affiliation: Affymax Research Institute, 3410 Central Expressway, Santa Clara, California 95051, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Szardenings
authors.forename: V
authors.initials: V
authors.lastname: Antonenko
authors.forename: D A
authors.initials: DA
authors.lastname: Campbell
authors.forename: N
authors.initials: N
authors.lastname: DeFrancisco
authors.forename: S
authors.initials: S
authors.lastname: Ida
authors.forename: L
authors.initials: L
authors.lastname: Shi
authors.forename: N
authors.initials: N
authors.lastname: Sharkov
authors.forename: D
authors.initials: D
authors.lastname: Tien
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Navre
mesh_terms: D015195:Drug Design; D020781:Matrix Metalloproteinase 1; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D010879:Piperazines; D011480:Protease Inhibitors; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1