Discovery of novel pyrrolopyridazine scaffolds as transient receptor potential vanilloid (TRPV1) antagonists.
A novel indolizine class of compounds was identified as TRPV1 antagonist from an HTS campaign. However, this indolizine class proved to be unstable and reacted readily with glutathione when exposed to light and oxygen. Reactivity was reduced by the introduction of a nitrogen atom alpha to the indolizine nitrogen. The pyrrolopyridazine core obtained proved to be inert to the action of light and oxygen. The synthesis route followed the one used for the indolizine compounds, and the potency and ADMET profile proved to be similar.
Medicinal Chemistry, CNSP iMed Science, AstraZeneca R&D, Innovative Medicines, SE-15185 Södertälje, Sweden. i.dorange@hotmail.com
Ismet
I
Dorange
Rickard
R
Forsblom
Istvan
I
Macsari
Mats
M
Svensson
Johan
J
Bylund
Yevgeni
Y
Besidski
Jan
J
Blid
Daniel
D
Sohn
Ylva
Y
Gravenfors
D000818:Animals; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006801:Humans; D054836:Indolizidines / Q000737:chemistry; D008862:Microsomes, Liver / Q000378:metabolism; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism
D054836:Indolizidines; D011724:Pyridazines; D011758:Pyrroles; C508945:Pyrrolopyridazine; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human