ABSTRACT
Pendrin is a transmembrane chloride/anion antiporter that is strongly upregulated in the airways in rhinoviral infection, asthma, cystic fibrosis and chronic rhinosinusitis. Based on its role in the regulation of airway surface liquid depth, pendrin inhibitors have potential indications for treatment of inflammatory airways diseases. Here, a completely regioselective route to tetrahydro-pyrazolopyridine pendrin inhibitors based on 1,3-diketone and substituted hydrazine condensation was been developed. Structure-activity relationships at the tetrahydropyridyl nitrogen were investigated using a focused library, establishing the privileged nature of N-phenyl ureas and improving inhibitor potency by greater than 2-fold.
Subject(s)
Pyrazoles/pharmacology , Pyridines/pharmacology , Sulfate Transporters/antagonists & inhibitors , Animals , Mice , Molecular Structure , Pyrazoles/chemical synthesis , Pyridines/chemical synthesis , Rats, Inbred F344 , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/pharmacology , Structure-Activity RelationshipABSTRACT
A concise, one-step route to indazolones from primary alkyl amines and o-nitrobenzyl alcohols is reported. The key step in this readily scalable indazolone forming process involves base-mediated in situ o-nitrobenzyl alcohol â o-nitrosobenzaldehyde conversion. Although this functional group interconversion is known to be useful for 2 H-indazole synthesis, its reactivity was modulated for indazolone formation.
