2. Academic Validation
  3. Discovery of potent, selective, and orally active carboxylic acid based inhibitors of matrix metalloproteinase-13

Discovery of potent, selective, and orally active carboxylic acid based inhibitors of matrix metalloproteinase-13

  • J Med Chem. 2009 Jun 11;52(11):3523-38. doi: 10.1021/jm801394m.
Lauren G Monovich 1,  Ruben A Tommasi,  Roger A Fujimoto,  Vincent Blancuzzi,  Kirk Clark,  Wendy D Cornell,  Robert Doti,  John Doughty,  James Fang,  David Farley,  John Fitt,  Vishwas Ganu,  Ronald Goldberg,  Robert Goldstein,  Stacey Lavoie,  Raviraj Kulathila,  William Macchia,  David T Parker,  Richard Melton,  Elizabeth O'Byrne,  Gary Pastor,  Theodore Pellas,  Elizabeth Quadros,  Noela Reel,  Dennis M Roland,  Yumi Sakane,  Hem Singh,  Jerry Skiles,  Joseph Somers,  Karen Toscano,  Andrew Wigg,  Siyuan Zhou,  Lijuan Zhu,  Wen-Chung Shieh,  Song Xue,  Leslie W McQuire
Affiliations

Affiliation

  • 1 Arthritis and Bone Metabolism Research, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
PMID: 19422229 DOI: 10.1021/jm801394m
Abstract

The matrix metalloproteinase Enzyme MMP-13 plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). An effective MMP-13 Inhibitor would therefore be a novel disease modifying therapy for the treatment of arthritis. Our efforts have resulted in the discovery of a series of carboxylic acid inhibitors of MMP-13 that do not significantly inhibit the related MMP-1 (collagenase-1) or tumor necrosis factor-alpha (TNF-alpha) converting Enzyme (TACE). It has previously been suggested (but not proven) that inhibition of the latter two Enzymes could lead to side effects. A promising carboxylic acid lead 9 was identified and a convergent synthesis developed. This paper describes the optimization of 9 and the identification of a compound 24f for further development. Compound 24f is a subnanomolar inhibitor of MMP-13 (IC(50) value 0.5 nM and K(i) of 0.19 nM) having no activity against MMP-1 or TACE (IC(50) of >10000 nM). Furthermore, in a rat model of MMP-13-induced cartilage degradation, 24f significantly reduced proteoglycan release following oral dosing at 30 mg/kg (75% inhibition, p < 0.05) and at 10 mg/kg (40% inhibition, p < 0.05).

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