title: Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis.
abstract: Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S(1)(') active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model.
authors.affiliation: Global Research and Development, Pfizer Inc., 700 Chesterfield Parkway West, St. Louis, MO 63017, USA. mark.e.schnute@pfizer.com
authors.forename: Mark E
authors.initials: ME
authors.lastname: Schnute
authors.forename: Patrick M
authors.initials: PM
authors.lastname: O'Brien
authors.forename: Joe
authors.initials: J
authors.lastname: Nahra
authors.forename: Mark
authors.initials: M
authors.lastname: Morris
authors.forename: W
authors.initials: W
authors.lastname: Howard Roark
authors.forename: Cathleen E
authors.initials: CE
authors.lastname: Hanau
authors.forename: Peter G
authors.initials: PG
authors.lastname: Ruminski
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Scholten
authors.forename: Theresa R
authors.initials: TR
authors.lastname: Fletcher
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Hamper
authors.forename: Jeffery N
authors.initials: JN
authors.lastname: Carroll
authors.forename: William C
authors.initials: WC
authors.lastname: Patt
authors.forename: Huey S
authors.initials: HS
authors.lastname: Shieh
authors.forename: Brandon
authors.initials: B
authors.lastname: Collins
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Pavlovsky
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Palmquist
authors.forename: Karl W
authors.initials: KW
authors.lastname: Aston
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hitchcock
authors.forename: Michael D
authors.initials: MD
authors.lastname: Rogers
authors.forename: Joseph
authors.initials: J
authors.lastname: McDonald
authors.forename: Adam R
authors.initials: AR
authors.lastname: Johnson
authors.forename: Grace E
authors.initials: GE
authors.lastname: Munie
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Wittwer
authors.forename: Chiu-Fai
authors.initials: CF
authors.lastname: Man
authors.forename: Steven L
authors.initials: SL
authors.lastname: Settle
authors.forename: Olga
authors.initials: O
authors.lastname: Nemirovskiy
authors.forename: Lillian E
authors.initials: LE
authors.lastname: Vickery
authors.forename: Arun
authors.initials: A
authors.lastname: Agawal
authors.forename: Richard D
authors.initials: RD
authors.lastname: Dyer
authors.forename: Teresa
authors.initials: T
authors.lastname: Sunyer
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001665:Binding Sites; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D055808:Drug Discovery; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D010003:Osteoarthritis / Q000188:drug therapy*; D010848:Picolinic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015032:Zinc / Q000737:chemistry
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D010848:Picolinic Acids; D011480:Protease Inhibitors; D013777:Tetrazoles; D053509:Matrix Metalloproteinase 13; D015032:Zinc