Potent, selective spiropyrrolidine pyrimidinetrione inhibitors of MMP-13.

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Freeman-Cook KD, Reiter LA, Noe MC, Antipas AS, Danley DE, Datta K, Downs JT, Eisenbeis S, Eskra JD, Garmene DJ, Greer EM, Griffiths RJ, Guzman R, Hardink JR, Janat F, Jones CS, Martinelli GJ, Mitchell PG, Laird ER, Liras JL, Lopresti-Morrow LL, Pandit J, Reilly UD, Robertson D, Vaughn-Bowser ML, Wolf-Gouviea LA, Yocum SA

Potent, selective spiropyrrolidine pyrimidinetrione inhibitors of MMP-13.

Bioorg Med Chem Lett. 2007 Dec 1;17(23):6529-34. Epub 2007 Sep 29.

PubMed ID

17935984 [ View in PubMed

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Abstract

Explorations in the pyrimidinetrione series of MMP-13 inhibitors led to the discovery of a series of spiro-fused compounds that are potent and selective inhibitors of MMP-13. While other spiro-fused motifs are hydrolytically unstable, presumably due to electronic destabilization of the pyrimidinetrione ring, the spiropyrrolidine series does not share this liability. Greater than 100-fold selectivity versus other MMP family members was achieved by incorporation of an extended aryl-heteroaryl P1'group. When dosed as the sodium salt, these compounds displayed excellent oral absorption and pharmacokinetic properties. Despite the selectivity, a representative of this series produced fibroplasia in a 14 day rat study.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
5-(2-ETHOXYETHYL)-5-[4-(4-FLUOROPHENOXY)PHENOXY]PYRIMIDINE-2,4,6(1H,3H,5H)-TRIONE	Collagenase 3	IC 50 (nM)	0.6	N/A	N/A	Details