Synthesis of a novel series of tricyclic dihydrofuran derivatives: discovery of 8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridines as melatonin receptor (MT1/MT2) ligands.
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Koike T, Takai T, Hoashi Y, Nakayama M, Kosugi Y, Nakashima M, Yoshikubo S, Hirai K, Uchikawa O
Synthesis of a novel series of tricyclic dihydrofuran derivatives: discovery of 8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridines as melatonin receptor (MT1/MT2) ligands.
J Med Chem. 2011 Jun 23;54(12):4207-18. doi: 10.1021/jm200385u. Epub 2011 May 24.
- PubMed ID
- 21568291 [ View in PubMed]
- Abstract
Novel tricyclic dihydrofuran derivatives were designed, synthesized, and evaluated as melatonin receptor (MT(1)/MT(2)) ligands based on the previously reported 1,6-dihydro-2H-indeno[5,4-b]furan 1a. By screening the central tricyclic cores, we identified 8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridine as a potent scaffold with a high ligand-lipophilicity efficiency (LLE) value. Subsequent optimization of the side chains led to identification of the potent MT(1)/MT(2) agonist 4d (MT(1), K(i) = 0.062 nM; MT(2), K(i) = 0.420 nM) with good oral absorption and blood-brain barrier (BBB) penetration in rats. The oral administration of compound 4d exhibited a sleep-promoting action in freely moving cats at 0.1 mg/kg.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Melatonin Melatonin receptor type 1A Ki (nM) 0.24 N/A N/A Details Melatonin Melatonin receptor type 1A EC 50 (nM) 0.026 N/A N/A Details Melatonin Melatonin receptor type 1B Ki (nM) 0.21 N/A N/A Details Melatonin Melatonin receptor type 1B EC 50 (nM) 0.82 N/A N/A Details