Potent pyrimidinetrione-based inhibitors of MMP-13 with enhanced selectivity over MMP-14.
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.
Blagg
Julian A
JA
Pfizer Global Research and Development, Groton Laboratories, MS8220-2471, Eastern Point Road, Groton, CT 06340, USA.
Noe
Mark C
MC
Wolf-Gouveia
Lilli A
LA
Reiter
Lawrence A
LA
Laird
Ellen R
ER
Chang
Shang-Poa P
SP
Danley
Dennis E
DE
Downs
James T
JT
Elliott
Nancy C
NC
Eskra
James D
JD
Griffiths
Richard J
RJ
Hardink
Joel R
JR
Haugeto
Amber I
AI
Jones
Christopher S
CS
Liras
Jennifer L
JL
Lopresti-Morrow
Lori L
LL
Mitchell
Peter G
PG
Pandit
Jayvardhan
J
Robinson
Ralph P
RP
Subramanyam
Chakrapani
C
Vaughn-Bowser
Marcie L
ML
Yocum
Sue A
SA
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
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D011743:Pyrimidines; D017364:Collagenases; D053509:Matrix Metalloproteinase 13