A Highly Selective Hydantoin Inhibitor of Aggrecanase-1 and Aggrecanase-2 with a Low Projected Human Dose
| Autor: | Kannan Thirunavukkarasu, Mark Chambers, Daniel R. Mudra, Michael Robert Wiley, Craig A. Swearingen, Lisa A. Adams, Timothy B. Durham, Jothirajah Marimuthu, C. Lin, James Lee Toth, Chin Liu |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Hydantoin Osteoarthritis Pharmacology 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Pharmacokinetics Drug Discovery medicine Animals Humans Aggrecans Enzyme Inhibitors IC50 Aggrecan Aggrecanase Metalloproteinase 010405 organic chemistry Hydantoins Cartilage medicine.disease Rats 0104 chemical sciences Molecular Docking Simulation 030104 developmental biology medicine.anatomical_structure chemistry Biochemistry Rats Inbred Lew ADAMTS4 Protein Molecular Medicine ADAMTS5 Protein |
| Zdroj: | Journal of Medicinal Chemistry. 60:5933-5939 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.7b00650 |
| Popis: | Aggrecanase-1 and -2 (ADAMTS-4 and ADAMTS-5) are zinc metalloproteases involved in the degradation of aggrecan in cartilage. Inhibitors could provide a means of altering the progression of osteoarthritis. We report the identification of 7 which had good oral pharmacokinetics in rats and showed efficacy in a rat chemical model of osteoarthritis. The projected human dose required to achieve sustained plasma levels ≥10 times the hADAMTS-5 IC50 is 5 mg q.d. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|