Potent, selective pyrimidinetrione-based inhibitors of MMP-13 |
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Authors: | Reiter Lawrence A Freeman-Cook Kevin D Jones Christopher S Martinelli Gary J Antipas Amy S Berliner Martin A Datta Kaushik Downs James T Eskra James D Forman Michael D Greer Elaine M Guzman Roberto Hardink Joel R Janat Fouad Keene Nandell F Laird Ellen R Liras Jennifer L Lopresti-Morrow Lori L Mitchell Peter G Pandit Jayvardhan Robertson Donald Sperger Diana Vaughn-Bowser Marcie L Waller Darra M Yocum Sue A |
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Institution: | Pfizer Global Research & Development, Groton Laboratories, Eastern Point Road, Groton, CT 06340, USA. lawrence.a.reiter@pfizer.com |
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Abstract: | 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. |
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