Hirosato Kondo — Page 2

PubMed2002

New strategy for antedrug application: development of metalloproteinase inhibitors as antipsoriatic drugs.

Phosphonamide-based inhibitors were synthesized and evaluated for the inhibitory activities against the shedding of epidermal growth factors, amphiregulin and heparin-binding EGF-like growth factor, that would participate in the development of psoriasis. All compounds exhibited excellent inhibitory activities for these EGF sheddings; however, they also inhibited matrix metalloproteinases (MMPs). To avoid adverse effects reported by the clinical development of MMP inhibitors, the antedrug concept was introduced. Among the phosphonamide inhibitors, the 2,2,2-trifluoroethyl ester 8d and 2,2-difluoroethyl ester 8c showed rapid decomposition in human plasma, which is an essential property for the antedrug. Topical applications of these compounds significantly suppressed TPA-induced epidermal hyperplasia in murin skin, a model of psoriasis. These results suggested that the phosphonamide-based inhibitors have a therapeutic potential for the treatment of psoriasis as an antedrug application.

Amphiregulin↗

PubMed2002

A three-dimensional quantitative structure-activity relationship study of heparin-binding epidermal growth factor shedding inhibitors using comparative molecular field analysis.

Despite the lack of structural information on the heparin-binding (HB) epidermal growth factor (EGF) shedding putative target enzyme, the design of potent HB-EGF shedding inhibitors has been attempted by means of comparative molecular field analysis (CoMFA), a well-established 3D-QSAR technique. Two different binding modes, obtained by docking a flexible representative into the MMP-3 and TACE target enzymes, were considered as alignment rules for an in-house data set of 50 HB-EGF shedding inhibitors. CoMFA models were derived with the standard steric, electrostatic, and Bohacek and McMartin's H-bond molecular fields. These fields were used individually or in combination. For both alignments, the H-bond field alone yielded the best statistical models. From the analysis of the CoMFA contours, ideas for testing the size of the S1' pocket and suggestions for the design of new inhibitors came forward, resulting in the synthesis and testing of four new inhibitors. Three of four compounds turned out to possess from good (IC(50) = 0.56 and 0.60 microM) to excellent (IC(50) = 0.13 microM) inhibitory activity. The hypothesis that, upon binding, the S1' pocket in the vicinity of the R(1) benzene ring must be narrow in size was confirmed by the weak activity (IC(50) = 1.1 microM) of the fourth compound. The experimental profile of these new inhibitors does suggest the MMP-3 alignment as the most plausible one for HB-EGF shedding inhibitors.

Epidermal Growth Factor↗

PubMed2002

Design and synthesis of dual inhibitors for matrix metalloproteinase and cathepsin.

The first example of dual inhibitors for matrix metalloproteinase (MMP) and cathepsin is described. An appropriate alignment of peptide-parts and two different specific functional groups in one molecule led to the discovery of a potent dual inhibitor (3a).

Cathepsin L↗