Design and Synthesis of Water-Soluble and Potent MMP-13 Inhibitors with Activity in Human Osteosarcoma Cells

oleh: Jose Maria Zapico, Lourdes Acosta, Miryam Pastor, Loganathan Rangasamy, Laura Marquez-Cantudo, Claire Coderch, Irene Ortin, Maria Nicolau-Sanus, Leonor Puchades-Carrasco, Antonio Pineda-Lucena, Alejandro Majali-Martinez, Pilar Ramos, Beatriz de Pascual-Teresa, Ana Ramos

Format: Article
Diterbitkan: MDPI AG 2021-09-01

Deskripsi

Osteoarthritis is a degenerative disease, often resulting in chronic joint pain and commonly affecting elderly people. Current treatments with anti-inflammatory drugs are palliative, making the discovery of new treatments necessary. The inhibition of matrix metalloproteinase <i>MMP-13</i> is a validated strategy to prevent the progression of this common joint disorder. We recently described polybrominated benzotriazole derivatives with nanomolar inhibitory activity and a promising selectivity profile against this collagenase. In this work, we have extended the study in order to explore the influence of bromine atoms and the nature of the S1′ heterocyclic interacting moiety on the solubility/selectivity balance of this type of compound. Drug target interactions have been assessed through a combination of molecular modeling studies and NMR experiments. Compound <b>9a</b> has been identified as a water-soluble and highly potent inhibitor with activity in MG-63 human osteosarcoma cells.