Jacobson, Kenneth (NIDDK)
Kiselev, Evgeny (NIGMS)
Uliassi, Elisa (NIDDK)
Junker, Anna (NIDDK)
The Molecular Recognition Section of NIDDK announces the availability of a novel triazole-based probes, structures which act as antagonists at human P2Y14 receptors. Although the physiologic functions of this receptor remain undefined, recently it has been strongly implicated in immune and inflammatory responses. Prior work with a 4,7-disubstituted 2 naphthoic acid derivative (PPTN) established the ability to inhibit chemotaxis of human neutrophils in the lung and kidney.
In this series, the triazole moiety is used as a bioisosteric replacement for the naphthoic acid core of PPTN. This substitution imparts more stability. This triazole ring has increased polarity and additional H-bond accepting groups when compared to a naphthalene core. The new triazole scaffold can form additional interactions that stabilize the ligand within the receptor binding pocket. It has also been identified that substitution at the para-position of the phenyl ring is favored.
- Probe to examine P2Y14 function.
- Scaffold for SAR studies and drug design.
- Potential route to target inflammation, potentially including diabetes and asthma.
- Favorable cLogP for lead compound when compared to PPTN.
- Wide range of functional groups can be used as terminal aryl substituents in the triazole group.
- P2Y14 affinity in the nM range.