Addressing species specific metabolism and solubility issues in a quinoline series of oral PDE4 inhibitors

Autor:	Lisa E. Ranshaw, Tracy Jane Shipley, Suzanne Elaine Keeling, Colin David Eldred, Nicola Mary Aston, B. Judkins, Ed Robinson, Kam Gohil, Naimisha Trivedi, Christopher James Lunniss, Andy Craven
Rok vydání:	2010
Předmět:	medicine.drug_class Metabolite Clinical Biochemistry Administration Oral Pharmaceutical Science Carboxamide Heterocyclic Compounds 2-Ring Biochemistry Structure-Activity Relationship chemistry.chemical_compound Pharmacokinetics Drug Discovery medicine Animals Solubility Molecular Biology Cinnoline biology Organic Chemistry Quinoline Cyclic Nucleotide Phosphodiesterases Type 4 Rats Bioavailability Macaca fascicularis chemistry Enzyme inhibitor Quinolines biology.protein Molecular Medicine Phosphodiesterase 4 Inhibitors
Zdroj:	Bioorganic & Medicinal Chemistry Letters. 20:137-140
ISSN:	0960-894X
DOI:	10.1016/j.bmcl.2009.11.010
Popis:	Species specific conversion of the lead PDE4 inhibitor 1 to the quinolone 3 was identified as the major route of metabolism in the cynomolgus monkey. Modification of the template to give the cinnoline 9 retained potency and selectivity, and greatly improved the pharmacokinetic profile in the cynomolgus monkey compared with 1. Additional SAR studies aimed at improving the solubility of 9 are also described.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::eb271e1e882da928f3b0ee05c4c9fb31 https://doi.org/10.1016/j.bmcl.2009.11.010 Zobrazit plný text záznamu Full Text from ScienceDirect