Potent, selective pyrimidinetrione-based inhibitors of MMP-13.
Reiter LA, Freeman-Cook KD, Jones CS, Martinelli GJ, Antipas AS, Berliner MA, Datta K, Downs JT, Eskra JD, Forman MD, Greer EM, Guzman R, Hardink JR, Janat F, Keene NF, Laird ER, Liras JL, Lopresti-Morrow LL, Mitchell PG, Pandit J, Robertson D, Sperger D, Vaughn-Bowser ML, Waller DM, Yocum SA.
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.