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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Szardenings AK,Antonenko V,Campbell DA,DeFrancisco N,Ida S,Shi L,Sharkov N,Tien D,Wang Y,Navre Mdoi
10.1021/jm980475pkeywords:
subject
Has Abstractpub_date
1999-04-22 00:00:00pages
1348-57issue
8eissn
0022-2623issn
1520-4804pii
jm980475pjournal_volume
42pub_type
杂志文章abstract：:A variety of derivatives of 2-pyridinecarboxaldehyde 1-oxide benzenesulfonylhydrazone, containing substituents on the benzene or pyridine rings as well as on the nitrogen atom which is bonded directly to the sulfonyl group, have been synthesized. The antineoplastic activity of these compounds has been assessed in mice...
journal_title：Journal of medicinal chemistry
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