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GKT-831 (formerly GKT137831) is a orally [[Bioavailability|bioavailable]] dual inhibitor of [[NADPH oxidase]] isoforms [[NOX4]] and [[NOX1]]. GKT-831 is a new chemical entity, member of the pyrazolopyridine dione chemical series. The compound is currently the lonely specific NOX inhibitor that has entered into clinical trials. GKT-831 has demonstrated biological activity in a number of in vitro and in vivo pharmacological models including [[diabetic nephropathy]], [[retinopathy]], [[atherosclerosis]], [[liver fibrosis]], [[osteoporosis]], [[pulmonary hypertension]] and [[idiopathic pulmonary fibrosis]]. GKT-831 is currently developed by Genkyotex, a French biotech company based in [[Toulouse]]. |
GKT-831 (formerly GKT137831) is a orally [[Bioavailability|bioavailable]] dual inhibitor of [[NADPH oxidase]] isoforms [[NOX4]] and [[NOX1]]. GKT-831 is a new chemical entity, member of the pyrazolopyridine dione chemical series. The compound is currently the lonely specific NOX inhibitor that has entered into clinical trials. GKT-831 has demonstrated biological activity in a number of in vitro and in vivo pharmacological models<ref>{{Cite journal|last=Deliyanti|first=Devy|last2=Wilkinson-Berka|first2=Jennifer L.|date=2015-07-30|title=Inhibition of NOX1/4 with GKT137831: a potential novel treatment to attenuate neuroglial cell inflammation in the retina|url=https://www.ncbi.nlm.nih.gov/pubmed/26219952|journal=Journal of Neuroinflammation|volume=12|pages=136|doi=10.1186/s12974-015-0363-z|issn=1742-2094|pmc=PMC4518508|pmid=26219952}}</ref><ref>{{Cite journal|last=Somanna|first=Naveen K.|last2=Valente|first2=Anthony J.|last3=Krenz|first3=Maike|last4=Fay|first4=William P.|last5=Delafontaine|first5=Patrice|last6=Chandrasekar|first6=Bysani|date=2016-05-01|title=The Nox1/4 Dual Inhibitor GKT137831 or Nox4 Knockdown Inhibits Angiotensin-II-Induced Adult Mouse Cardiac Fibroblast Proliferation and Migration. AT1 Physically Associates With Nox4|url=https://www.ncbi.nlm.nih.gov/pubmed/26445208|journal=Journal of Cellular Physiology|volume=231|issue=5|pages=1130–1141|doi=10.1002/jcp.25210|issn=1097-4652|pmc=PMC5237386|pmid=26445208}}</ref><ref>{{Cite journal|last=Asensio-López|first=Mari C.|last2=Soler|first2=Fernando|last3=Sánchez-Más|first3=Jesús|last4=Pascual-Figal|first4=Domingo|last5=Fernández-Belda|first5=Francisco|last6=Lax|first6=Antonio|date=2016-03-15|title=Early oxidative damage induced by doxorubicin: Source of production, protection by GKT137831 and effect on Ca(2+) transporters in HL-1 cardiomyocytes|url=https://www.ncbi.nlm.nih.gov/pubmed/26906075|journal=Archives of Biochemistry and Biophysics|volume=594|pages=26–36|doi=10.1016/j.abb.2016.02.021|issn=1096-0384|pmid=26906075}}</ref><ref>{{Cite journal|last=Gray|first=Stephen P.|last2=Jha|first2=Jay C.|last3=Kennedy|first3=Kit|last4=van Bommel|first4=Erik|last5=Chew|first5=Phyllis|last6=Szyndralewiez|first6=Cedric|last7=Touyz|first7=Rhian M.|last8=Schmidt|first8=Harald H. H. W.|last9=Cooper|first9=Mark E.|date=2017-05-01|title=Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease|url=https://www.ncbi.nlm.nih.gov/pubmed/28160092|journal=Diabetologia|volume=60|issue=5|pages=927–937|doi=10.1007/s00125-017-4215-5|issn=1432-0428|pmid=28160092}}</ref> including [[diabetic nephropathy]], [[retinopathy]], [[atherosclerosis]], [[liver fibrosis]], [[osteoporosis]], [[pulmonary hypertension]] and [[idiopathic pulmonary fibrosis]]. GKT-831 is currently developed by Genkyotex, a French biotech company based in [[Toulouse]]. |
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==Strategy of Development== |
==Strategy of Development== |
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Revision as of 14:20, 14 May 2017
Template:New unreviewed article
GKT-831 (formerly GKT137831) is a orally bioavailable dual inhibitor of NADPH oxidase isoforms NOX4 and NOX1. GKT-831 is a new chemical entity, member of the pyrazolopyridine dione chemical series. The compound is currently the lonely specific NOX inhibitor that has entered into clinical trials. GKT-831 has demonstrated biological activity in a number of in vitro and in vivo pharmacological models[1][2][3][4] including diabetic nephropathy, retinopathy, atherosclerosis, liver fibrosis, osteoporosis, pulmonary hypertension and idiopathic pulmonary fibrosis. GKT-831 is currently developed by Genkyotex, a French biotech company based in Toulouse.
Strategy of Development
The strategy of development of GKT-831 was initially focused on the treatment of fibrosis and particularly idiopathic pulmonary fibrosis (IPF), a life threatening disease. GKT-831 obtained orphan drug designation from regulatory agencies in US and EU in early 2010. Despite excellent in vitro and in vivo pharmacology results obtained in preclinical pharmacological models of fibrosis and IPF, and promising phase 1 data showing low toxicity of GKT-831, the company Genkyotex decided to initiate a phase 2 Proof-of-concept in the complex indication of diabetic nephropathy in 2014. As a result, GKT-831 did not reach primary clinical end point and the compound failed to make any significant reduction in albuminuria. Thereafter, the company decided to refocus development to initial clinical applications in fibrosis. In May 2017, Genkyotex announced FDA approval of IND for phase 2 clinical trials in patients with primary biliary cholangitis with extended treatment duration and large study size potentially allowing to assess the effects of GKT-831 on liver inflammation and fibrosis.
History
GKT-831 was discovered in early 2000s by scientists at Genkyotex and invented by a team led by Dr. Patrick Page. The compound was patented in 2007 by Genkyotex. GKT-831 was initially developed for Idiopathic pulmonary fibrosis and obtained orphan drug designation both by FDA and EMEA by end of 2010. GKT-831 was developed by rational drug design following a campaign of high-throughput screening on several NOX isoforms. The initial lead compound GKT136901, a pyrazolopyridine dione derivative was further structurally modified in order to enhance binding affinity and improve pharmacokinetic properties, resulting in the discovery of GKT-831.
References
- ^ Deliyanti, Devy; Wilkinson-Berka, Jennifer L. (2015-07-30). "Inhibition of NOX1/4 with GKT137831: a potential novel treatment to attenuate neuroglial cell inflammation in the retina". Journal of Neuroinflammation. 12: 136. doi:10.1186/s12974-015-0363-z. ISSN 1742-2094. PMC 4518508. PMID 26219952.
{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link) - ^ Somanna, Naveen K.; Valente, Anthony J.; Krenz, Maike; Fay, William P.; Delafontaine, Patrice; Chandrasekar, Bysani (2016-05-01). "The Nox1/4 Dual Inhibitor GKT137831 or Nox4 Knockdown Inhibits Angiotensin-II-Induced Adult Mouse Cardiac Fibroblast Proliferation and Migration. AT1 Physically Associates With Nox4". Journal of Cellular Physiology. 231 (5): 1130–1141. doi:10.1002/jcp.25210. ISSN 1097-4652. PMC 5237386. PMID 26445208.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Asensio-López, Mari C.; Soler, Fernando; Sánchez-Más, Jesús; Pascual-Figal, Domingo; Fernández-Belda, Francisco; Lax, Antonio (2016-03-15). "Early oxidative damage induced by doxorubicin: Source of production, protection by GKT137831 and effect on Ca(2+) transporters in HL-1 cardiomyocytes". Archives of Biochemistry and Biophysics. 594: 26–36. doi:10.1016/j.abb.2016.02.021. ISSN 1096-0384. PMID 26906075.
- ^ Gray, Stephen P.; Jha, Jay C.; Kennedy, Kit; van Bommel, Erik; Chew, Phyllis; Szyndralewiez, Cedric; Touyz, Rhian M.; Schmidt, Harald H. H. W.; Cooper, Mark E. (2017-05-01). "Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease". Diabetologia. 60 (5): 927–937. doi:10.1007/s00125-017-4215-5. ISSN 1432-0428. PMID 28160092.