title: Potent, selective spiropyrrolidine pyrimidinetrione inhibitors of MMP-13.
abstract: Explorations in the pyrimidinetrione series of MMP-13 inhibitors led to the discovery of a series of spiro-fused compounds that are potent and selective inhibitors of MMP-13. While other spiro-fused motifs are hydrolytically unstable, presumably due to electronic destabilization of the pyrimidinetrione ring, the spiropyrrolidine series does not share this liability. Greater than 100-fold selectivity versus other MMP family members was achieved by incorporation of an extended aryl-heteroaryl P1'group. When dosed as the sodium salt, these compounds displayed excellent oral absorption and pharmacokinetic properties. Despite the selectivity, a representative of this series produced fibroplasia in a 14 day rat study.
authors.affiliation: Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. Kevin.Freeman-cook@pfizer.com
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Freeman-Cook
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Reiter
authors.forename: Mark C
authors.initials: MC
authors.lastname: Noe
authors.forename: Amy S
authors.initials: AS
authors.lastname: Antipas
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Danley
authors.forename: Kaushik
authors.initials: K
authors.lastname: Datta
authors.forename: James T
authors.initials: JT
authors.lastname: Downs
authors.forename: Shane
authors.initials: S
authors.lastname: Eisenbeis
authors.forename: James D
authors.initials: JD
authors.lastname: Eskra
authors.forename: David J
authors.initials: DJ
authors.lastname: Garmene
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Greer
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Griffiths
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: Christopher S
authors.initials: CS
authors.lastname: Jones
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Martinelli
authors.forename: Peter G
authors.initials: PG
authors.lastname: Mitchell
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: Jayvardhan
authors.initials: J
authors.lastname: Pandit
authors.forename: Usa D
authors.initials: UD
authors.lastname: Reilly
authors.forename: Donald
authors.initials: D
authors.lastname: Robertson
authors.forename: Marcie L
authors.initials: ML
authors.lastname: Vaughn-Bowser
authors.forename: Lilli A
authors.initials: LA
authors.lastname: Wolf-Gouviea
authors.forename: Sue A
authors.initials: SA
authors.lastname: Yocum
mesh_terms: D000818:Animals; D004795:Enzyme Stability / Q000187:drug effects; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011743:Pyrimidines; D011759:Pyrrolidines; D013141:Spiro Compounds; D053509:Matrix Metalloproteinase 13