title: Discovery of N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)-5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide. A Highly Selective and Orally Bioavailable Matrix Metalloproteinase-13 Inhibitor for the Potential Treatment of Osteoarthritis.
abstract: Matrix metalloproteinase-13 (MMP-13) is a zinc-dependent protease responsible for the cleavage of type II collagen, the major structural protein of articular cartilage. Degradation of this cartilage matrix leads to the development of osteoarthritis. We previously have described highly potent and selective carboxylic acid containing MMP-13 inhibitors; however, nephrotoxicity in preclinical toxicology species precluded development. The accumulation of compound in the kidneys mediated by human organic anion transporter 3 (hOAT3) was hypothesized as a contributing factor for the finding. Herein we report our efforts to optimize the MMP-13 potency and pharmacokinetic properties of non-carboxylic acid leads resulting in the identification of compound 43a lacking the previously observed preclinical toxicology at comparable exposures.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Ruminski
authors.forename: Mark
authors.initials: M
authors.lastname: Massa
authors.forename: Joseph
authors.initials: J
authors.lastname: Strohbach
authors.forename: Cathleen E
authors.initials: CE
authors.lastname: Hanau
authors.forename: Michelle
authors.initials: M
authors.lastname: Schmidt
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: Huey S
authors.initials: HS
authors.lastname: Shieh
authors.forename: Nicole
authors.initials: N
authors.lastname: Caspers
authors.forename: Brandon
authors.initials: B
authors.lastname: Collins
authors.forename: Margaret
authors.initials: M
authors.lastname: Grapperhaus
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Palmquist
authors.forename: Joe
authors.initials: J
authors.lastname: Collins
authors.forename: John E
authors.initials: JE
authors.lastname: Baldus
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hitchcock
authors.forename: H Peter
authors.initials: HP
authors.lastname: Kleine
authors.forename: Michael D
authors.initials: MD
authors.lastname: Rogers
authors.forename: Joseph
authors.initials: J
authors.lastname: McDonald
authors.forename: Grace E
authors.initials: GE
authors.lastname: Munie
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Pfizer , 700 North Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Dean M
authors.initials: DM
authors.lastname: Messing
authors.affiliation: Pharmacokinetics, Dynamics, and Metabolism, Pfizer , 700 North Main Street, Cambridge, Massachusetts 02139, United States.
authors.forename: Silvia
authors.initials: S
authors.lastname: Portolan
authors.affiliation: Drug Safety, Pfizer , 1 Burtt Road, Andover, Massachusetts 01810, United States.
authors.forename: Laurence O
authors.initials: LO
authors.lastname: Whiteley
authors.forename: Teresa
authors.initials: T
authors.lastname: Sunyer
authors.forename: Mark E
authors.initials: ME
authors.lastname: Schnute
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000473:pathology; D017364:Collagenases / Q000187:drug effects; D004285:Dogs; D015195:Drug Design; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D053509:Matrix Metalloproteinase 13 / Q000187:drug effects*; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D008958:Models, Molecular; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D010003:Osteoarthritis / Q000188:drug therapy*; D011485:Protein Binding; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D029362:Organic Anion Transporters, Sodium-Independent; C553448:PF152 compound; D011743:Pyrimidines; D013777:Tetrazoles; C114338:organic anion transport protein 3; D017364:Collagenases; D053509:Matrix Metalloproteinase 13