Potent, selective pyrimidinetrione-based inhibitors of MMP-13.
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.
Reiter
Lawrence A
LA
Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. lawrence.a.reiter@pfizer.com
Freeman-Cook
Kevin D
KD
Jones
Christopher S
CS
Martinelli
Gary J
GJ
Antipas
Amy S
AS
Berliner
Martin A
MA
Datta
Kaushik
K
Downs
James T
JT
Eskra
James D
JD
Forman
Michael D
MD
Greer
Elaine M
EM
Guzman
Roberto
R
Hardink
Joel R
JR
Janat
Fouad
F
Keene
Nandell F
NF
Laird
Ellen R
ER
Liras
Jennifer L
JL
Lopresti-Morrow
Lori L
LL
Mitchell
Peter G
PG
Pandit
Jayvardhan
J
Robertson
Donald
D
Sperger
Diana
D
Vaughn-Bowser
Marcie L
ML
Waller
Darra M
DM
Yocum
Sue A
SA
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
D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D011744:Pyrimidinones; D012492:Salts; D012964:Sodium