title: Potent pyrimidinetrione-based inhibitors of MMP-13 with enhanced selectivity over MMP-14.
abstract: Through the use of computational modeling, a series of pyrimidinetrione-based inhibitors of MMP-13 was designed based on a lead inhibitor identified through file screening. Incorporation of a biaryl ether moiety at the C-5 position of the pyrimidinetrione ring resulted in a dramatic enhancement of MMP-13 potency. Protein crystallography revealed that this moiety binds in the S(1)(') pocket of the enzyme. Optimization of the C-4 substituent of the terminal aromatic ring led to incorporation of selectivity versus MMP-14 (MT-1 MMP). Structure activity relationships of the biaryl ether substituent are presented as is pharmacokinetic data for a compound that meets our in vitro potency and selectivity goals.
authors.affiliation: Pfizer Global Research and Development, Groton Laboratories, MS8220-2471, Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Julian A
authors.initials: JA
authors.lastname: Blagg
authors.forename: Mark C
authors.initials: MC
authors.lastname: Noe
authors.forename: Lilli A
authors.initials: LA
authors.lastname: Wolf-Gouveia
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Reiter
authors.forename: Ellen R
authors.initials: ER
authors.lastname: Laird
authors.forename: Shang-Poa P
authors.initials: SP
authors.lastname: Chang
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Danley
authors.forename: James T
authors.initials: JT
authors.lastname: Downs
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Elliott
authors.forename: James D
authors.initials: JD
authors.lastname: Eskra
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Griffiths
authors.forename: Joel R
authors.initials: JR
authors.lastname: Hardink
authors.forename: Amber I
authors.initials: AI
authors.lastname: Haugeto
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Jones
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: Ralph P
authors.initials: RP
authors.lastname: Robinson
authors.forename: Chakrapani
authors.initials: C
authors.lastname: Subramanyam
authors.forename: Marcie L
authors.initials: ML
authors.lastname: Vaughn-Bowser
authors.forename: Sue A
authors.initials: SA
authors.lastname: Yocum
mesh_terms: D001665:Binding Sites; D017364:Collagenases / Q000737:chemistry; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D011743:Pyrimidines / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D011743:Pyrimidines; D017364:Collagenases; D053509:Matrix Metalloproteinase 13