Limits...
New strategies for targeting matrix metalloproteinases.

Fields GB - Matrix Biol. (2015)

Bottom Line: The development of matrix metalloproteinase (MMP) inhibitors has often been frustrated by a lack of specificity and subsequent off-target effects.Antibody-based approaches have resulted in selective inhibitors for MMP-9 and MT1-MMP that target CAT domain exosites.A variety of non-traditional approaches that incorporate exosite binding into the design process has yielded inhibitors with desirable selectivities within the MMP family.

View Article: PubMed Central - PubMed

Affiliation: Florida Atlantic University, Department of Chemistry & Biochemistry, 5353 Parkside Drive, Building MC17, Jupiter, FL 33458, United States; The Scripps Research Institute/Scripps Florida, Department of Chemistry, 130 Scripps Way, Jupiter, FL 33458, United States; Torrey Pines Institute for Molecular Studies, Department of Chemistry, 11350 SW Village Parkway, Port St. Lucie, FL 34987, United States; Torrey Pines Institute for Molecular Studies, Department of Biology, 11350 SW Village Parkway, Port St. Lucie, FL 34987, United States. Electronic address: fieldsg@fau.edu.

No MeSH data available.


Structures, from top to bottom, of (E)-4-((1-methyl-2,4-dioxo-6-(3-phenylprop-1-enyl)-1,2-dihydroqui-nazolin-3(4H)-yl)methyl)benzoic acid, reported by Pfizer as Compound 2 [24], compound Q/4 (2-[(4-chlorobenzyl)thio]-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one) [37], compound Q1/20 (2-[(4-methylphenyl)methyl sulfanyl]-1,5,6,7-tetrahydrocyclopenta[d]pyrimidin-4-one) [38], compound Q2/24 (methyl 4-[(4-oxo-1,5,6,7-tetrahydrocyclo penta[d]pyrimidin-2-yl)sulfanylmethyl] benzoate) [38], and N4,N6-bis(4-fluoro-3-methylbenzyl)pyrimidine-4,6-dicarboxamide, reported by Aventis as Compound 4 [22].
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4466128&req=5

Figure 2: Structures, from top to bottom, of (E)-4-((1-methyl-2,4-dioxo-6-(3-phenylprop-1-enyl)-1,2-dihydroqui-nazolin-3(4H)-yl)methyl)benzoic acid, reported by Pfizer as Compound 2 [24], compound Q/4 (2-[(4-chlorobenzyl)thio]-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one) [37], compound Q1/20 (2-[(4-methylphenyl)methyl sulfanyl]-1,5,6,7-tetrahydrocyclopenta[d]pyrimidin-4-one) [38], compound Q2/24 (methyl 4-[(4-oxo-1,5,6,7-tetrahydrocyclo penta[d]pyrimidin-2-yl)sulfanylmethyl] benzoate) [38], and N4,N6-bis(4-fluoro-3-methylbenzyl)pyrimidine-4,6-dicarboxamide, reported by Aventis as Compound 4 [22].

Mentions: Although selective MMP-13 inhibitors have been described by Alantos, Aventis, Boehringer, Pfizer, and Wyeth, important pharmacokinetic (PK) and/or other data have not been reported for many of these compounds, and no clinical studies have appeared. For example, no PK or MSS data has been reported for the Aventis and Wyeth compounds [22,30]. The first series of Pfizer compounds, while exhibiting good PK and MSS data, were tested against a limited number of MMPs [31–33]. In similar fashion, the Boehringer compounds exhibited good PK data but were tested against a limited number of MMPs, and not at all in a MSS model [34,35]. The Alantos compounds exhibited excellent MMP selectivity and good PK data, but were not tested in a MSS model [28,29]. Only the second series of Pfizer compounds were reported to exhibit excellent MMP selectivity and good PK and MSS data [24,25,27]. However, as mentioned above, no clinical studies have been reported for the Pfizer compounds. In our hands, we found the primary Pfizer compound (E)-4-((1-methyl-2,4-dioxo-6-(3-phenylprop-1-enyl)-1,2-dihydroquinazolin-3(4H)-yl)methyl)-benzoic acid (Fig. 2) to have low solubility (it could only be tested at a maximal concentration of 2.5 μM), and it inhibited cytochrome P450 1A2 [36].


New strategies for targeting matrix metalloproteinases.

Fields GB - Matrix Biol. (2015)

Structures, from top to bottom, of (E)-4-((1-methyl-2,4-dioxo-6-(3-phenylprop-1-enyl)-1,2-dihydroqui-nazolin-3(4H)-yl)methyl)benzoic acid, reported by Pfizer as Compound 2 [24], compound Q/4 (2-[(4-chlorobenzyl)thio]-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one) [37], compound Q1/20 (2-[(4-methylphenyl)methyl sulfanyl]-1,5,6,7-tetrahydrocyclopenta[d]pyrimidin-4-one) [38], compound Q2/24 (methyl 4-[(4-oxo-1,5,6,7-tetrahydrocyclo penta[d]pyrimidin-2-yl)sulfanylmethyl] benzoate) [38], and N4,N6-bis(4-fluoro-3-methylbenzyl)pyrimidine-4,6-dicarboxamide, reported by Aventis as Compound 4 [22].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466128&req=5

Figure 2: Structures, from top to bottom, of (E)-4-((1-methyl-2,4-dioxo-6-(3-phenylprop-1-enyl)-1,2-dihydroqui-nazolin-3(4H)-yl)methyl)benzoic acid, reported by Pfizer as Compound 2 [24], compound Q/4 (2-[(4-chlorobenzyl)thio]-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one) [37], compound Q1/20 (2-[(4-methylphenyl)methyl sulfanyl]-1,5,6,7-tetrahydrocyclopenta[d]pyrimidin-4-one) [38], compound Q2/24 (methyl 4-[(4-oxo-1,5,6,7-tetrahydrocyclo penta[d]pyrimidin-2-yl)sulfanylmethyl] benzoate) [38], and N4,N6-bis(4-fluoro-3-methylbenzyl)pyrimidine-4,6-dicarboxamide, reported by Aventis as Compound 4 [22].
Mentions: Although selective MMP-13 inhibitors have been described by Alantos, Aventis, Boehringer, Pfizer, and Wyeth, important pharmacokinetic (PK) and/or other data have not been reported for many of these compounds, and no clinical studies have appeared. For example, no PK or MSS data has been reported for the Aventis and Wyeth compounds [22,30]. The first series of Pfizer compounds, while exhibiting good PK and MSS data, were tested against a limited number of MMPs [31–33]. In similar fashion, the Boehringer compounds exhibited good PK data but were tested against a limited number of MMPs, and not at all in a MSS model [34,35]. The Alantos compounds exhibited excellent MMP selectivity and good PK data, but were not tested in a MSS model [28,29]. Only the second series of Pfizer compounds were reported to exhibit excellent MMP selectivity and good PK and MSS data [24,25,27]. However, as mentioned above, no clinical studies have been reported for the Pfizer compounds. In our hands, we found the primary Pfizer compound (E)-4-((1-methyl-2,4-dioxo-6-(3-phenylprop-1-enyl)-1,2-dihydroquinazolin-3(4H)-yl)methyl)-benzoic acid (Fig. 2) to have low solubility (it could only be tested at a maximal concentration of 2.5 μM), and it inhibited cytochrome P450 1A2 [36].

Bottom Line: The development of matrix metalloproteinase (MMP) inhibitors has often been frustrated by a lack of specificity and subsequent off-target effects.Antibody-based approaches have resulted in selective inhibitors for MMP-9 and MT1-MMP that target CAT domain exosites.A variety of non-traditional approaches that incorporate exosite binding into the design process has yielded inhibitors with desirable selectivities within the MMP family.

View Article: PubMed Central - PubMed

Affiliation: Florida Atlantic University, Department of Chemistry & Biochemistry, 5353 Parkside Drive, Building MC17, Jupiter, FL 33458, United States; The Scripps Research Institute/Scripps Florida, Department of Chemistry, 130 Scripps Way, Jupiter, FL 33458, United States; Torrey Pines Institute for Molecular Studies, Department of Chemistry, 11350 SW Village Parkway, Port St. Lucie, FL 34987, United States; Torrey Pines Institute for Molecular Studies, Department of Biology, 11350 SW Village Parkway, Port St. Lucie, FL 34987, United States. Electronic address: fieldsg@fau.edu.

No MeSH data available.