title: Potent, selective pyrimidinetrione-based inhibitors of MMP-13.
abstract: Using SAR from two related series of pyrimidinetrione-based inhibitors, compounds with potent MMP-13 inhibition and >100-fold selectivity against other MMPs have been identified. Despite high molecular weights, clogPs, and polar surface areas, the compounds are generally well absorbed and have excellent pharmacokinetic (PK) properties when dosed as sodium salts. In a rat fibrosis model, a compound from the series displayed no fibrosis at exposures many fold greater than its MMP-13 IC50.
authors.affiliation: Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. lawrence.a.reiter@pfizer.com
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Reiter
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Freeman-Cook
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Jones
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Martinelli
authors.forename: Amy S
authors.initials: AS
authors.lastname: Antipas
authors.forename: Martin A
authors.initials: MA
authors.lastname: Berliner
authors.forename: Kaushik
authors.initials: K
authors.lastname: Datta
authors.forename: James T
authors.initials: JT
authors.lastname: Downs
authors.forename: James D
authors.initials: JD
authors.lastname: Eskra
authors.forename: Michael D
authors.initials: MD
authors.lastname: Forman
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Greer
authors.forename: Roberto
authors.initials: R
authors.lastname: Guzman
authors.forename: Joel R
authors.initials: JR
authors.lastname: Hardink
authors.forename: Fouad
authors.initials: F
authors.lastname: Janat
authors.forename: Nandell F
authors.initials: NF
authors.lastname: Keene
authors.forename: Ellen R
authors.initials: ER
authors.lastname: Laird
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Liras
authors.forename: Lori L
authors.initials: LL
authors.lastname: Lopresti-Morrow
authors.forename: Peter G
authors.initials: PG
authors.lastname: Mitchell
authors.forename: Jayvardhan
authors.initials: J
authors.lastname: Pandit
authors.forename: Donald
authors.initials: D
authors.lastname: Robertson
authors.forename: Diana
authors.initials: D
authors.lastname: Sperger
authors.forename: Marcie L
authors.initials: ML
authors.lastname: Vaughn-Bowser
authors.forename: Darra M
authors.initials: DM
authors.lastname: Waller
authors.forename: Sue A
authors.initials: SA
authors.lastname: Yocum
mesh_terms: D000818:Animals; D005355:Fibrosis / Q000188:drug therapy / Q000473:pathology; D006877:Hydroxamic Acids / Q000737:chemistry; D020128:Inhibitory Concentration 50; D061965:Matrix Metalloproteinase Inhibitors; D008970:Molecular Weight; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011744:Pyrimidinones / Q000737:chemistry*; D051381:Rats; D012492:Salts / Q000737:chemistry; D012964:Sodium / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011744:Pyrimidinones; D012492:Salts; D012964:Sodium