236403-46-6Relevant academic research and scientific papers
A three-dimensional quantitative structure-activity relationship study of heparin-binding epidermal growth factor shedding inhibitors using comparative molecular field analysis
Bursi, Roberta,Sawa, Masaaki,Hiramatsu, Yasuyuki,Kondo, Hirosato
, p. 781 - 788 (2002)
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 (IC50= 0.56 and 0.60 μM) to excellent (IC50 = 0.13 μM) inhibitory activity. The hypothesis that, upon binding, the S1′ pocket in the vicinity of the R1 benzene ring must be narrow in size was confirmed by the weak activity (IC50 = 1.1 μM) 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.
Tetrahydroisoquinoline-3-carboxylate based matrix-metalloproteinase inhibitors: Design, synthesis and structure-activity relationship
Matter, Hans,Schudok, Manfred,Schwab, Wilfried,Thorwart, Werner,Barbier, Denis,Billen, Guenter,Haase, Burkhard,Neises, Bernhard,Weithmann, Klaus-Ulrich,Wollmann, Theo
, p. 3529 - 3544 (2007/10/03)
The design, synthesis and structure-activity relationship (SAR) of a series of nonpeptidic 2-arylsulfonyl-1,2,3,4-tetrahydro-isoquinoline-3-carboxylates and-hydroxamates as inhibitors of the matrix metalloproteinase human neutrophil collagenase (MMP-8) is described here. Based on available X-ray structures of MMP-8/inhibitor complexes, our structure-based design strategy was directed to complement major protein-ligand interaction regions mainly in the S1′ hydrophobic specificity pocket close to the catalytic zinc ion. Here, the rigid 1,2,3,4-tetrahydroisoquinoline scaffold (Tic) provides ideal geometry to combine hydroxamates and carboxylates as typical zinc complexing functionalities, with a broad variety of S1′ directed mono- and biaryl substituents consisting of aromatic rings perfectly accommodated within this more hydrophobic region of the MMP-8 inhibitor binding site. The effect of different S1′ directed substituents, zinc-complexing groups, chirality and variations of the tetrahydroisoquinoline ring-system is investigated by systematic studies. X-ray structure analyses in combination with 3D-QSAR studies provided an additional understanding of key determinants for MMP-8 affinity in this series. The hypothetical binding mode for a typical molecule as basis for our inhibitor design was found in good agreement with a 1.7 A X-ray structure of this candidate in complex with the catalytic domain of human MMP-8. After analysis of all systematic variations, 3D-QSAR and X-ray structure analysis, novel S1′ directed substituents were designed and synthesized and biologically evaluated. This finally results in inhibitors, which do not only show high biological affinity for MMP-8, but also exhibit good oral bioavailability in several animal species.
