title: Discovery of Novel, Highly Potent, and Selective Matrix Metalloproteinase (MMP)-13 Inhibitors with a 1,2,4-Triazol-3-yl Moiety as a Zinc Binding Group Using a Structure-Based Design Approach.
abstract: On the basis of a superposition study of X-ray crystal structures of complexes of quinazoline derivative 1 and triazole derivative 2 with matrix metalloproteinase (MMP)-13 catalytic domain, a novel series of fused pyrimidine compounds which possess a 1,2,4-triazol-3-yl group as a zinc binding group (ZBG) was designed. Among the herein described and evaluated compounds, 31f exhibited excellent potency for MMP-13 (IC50= 0.036 nM) and selectivities (greater than 1,500-fold) over other MMPs (MMP-1, -2, -3, -7, -8, -9, -10, and -14) and tumor necrosis factor-α converting enzyme (TACE). Furthermore, the inhibitor was shown to protect bovine nasal cartilage explants against degradation induced by interleukin-1 and oncostatin M. In this article, we report the discovery of extremely potent, highly selective, and orally bioavailable fused pyrimidine derivatives that possess a 1,2,4-triazol-3-yl group as a novel ZBG for selective MMP-13 inhibition.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 2-26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hiroshi
authors.identifier: 0000-0001-6770-2750
authors.initials: H
authors.lastname: Nara
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 2-26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kaieda
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 2-26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Sato
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 2-26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Naito
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 2-26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Mototani
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 2-26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Oki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 2-26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 2-26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Kuno
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 2-26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Santou
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 2-26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 2-26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Terauchi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 2-26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Uchikawa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 2-26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Masakuni
authors.initials: M
authors.lastname: Kori
mesh_terms: D000818:Animals; D002356:Cartilage / Q000378:metabolism; D002417:Cattle; D002614:Chelating Agents / Q000138:chemical synthesis / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism; D015195:Drug Design; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology*; D014230:Triazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D015032:Zinc / Q000737:chemistry*
chemical_list: C000620969:5-(3-fluorophenyl)-4-oxo-N-(3-(2-(1H-1,2,4-triazol-3-yloxy)ethoxy)benzyl)-3,4-dihydro-thieno(2,3-d)pyrimidine-2-carboxamide; D002614:Chelating Agents; D061965:Matrix Metalloproteinase Inhibitors; D011743:Pyrimidines; D011744:Pyrimidinones; D011799:Quinazolines; D013876:Thiophenes; D014230:Triazoles; D003094:Collagen; D053509:Matrix Metalloproteinase 13; D015032:Zinc