Development of autotaxin inhibitors: A series of tetrazole cinnamides

Autor:	Mark Freeman, Victoria Head, Binesh Shrestha, Michael Faller, Elizabeth Hardaker, Mark R Dowling, Rene Hemmig, Lucy Elphick, Johan C. Hill, Darren Le Grand, David D. Pascoe, Florence Zink, Christopher Thomson, Andrew Lister, S. Rieffel, David Beattie, Oliver Ross Steward
Rok vydání:	2020
Předmět:	Models Molecular Clinical Biochemistry hERG Pharmaceutical Science Tetrazoles 01 natural sciences Biochemistry chemistry.chemical_compound Mice Structure-Activity Relationship Drug Development In vivo Drug Discovery Animals Humans Tetrazole Enzyme Inhibitors Molecular Biology PK/PD models biology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Phosphoric Diester Hydrolases Organic Chemistry Combinatorial chemistry Amides 0104 chemical sciences Rats 010404 medicinal & biomolecular chemistry chemistry Cinnamates Lipophilicity biology.protein Microsome Molecular Medicine Autotaxin Selectivity
Zdroj:	Bioorganicmedicinal chemistry letters. 31
ISSN:	1464-3405
Popis:	A series of inhibitors of Autotaxin (ATX) have been developed from a high throughput screening hit, 1a, which shows an alternative binding mode to known catalytic site inhibitors. Selectivity over the hERG channel and microsomal clearance were dependent on the lipophilicity of the compounds, and this was optimised by reduction of clogD whilst maintaining high affinity ATX inhibition. Compound 15a shows good oral exposure, and concentration dependent inhibition of formation of LPA in vivo, as shown in pharmacokinetic-pharmacodynamic (PK/PD) experiments.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::02e384195e054e5c4b466872e8c04973 https://pubmed.ncbi.nlm.nih.gov/33160025 Zobrazit plný text záznamu Full Text from ScienceDirect