Novel orexin receptor agonists based on arene- or pyridine-fused 1,3-dihydro-2H-imidazole-2-imines.

Autor: Wang W; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9038, USA., Ranjan A; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9038, USA., Zhang W; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9038, USA., Liang Q; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9038, USA., MacMillan KS; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9038, USA., Chapman K; Department of Biophysics, University of Texas Southwestern Medical Center, 6001 Forest Park Rd., Dallas, TX 75390-9041, USA., Wang X; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9038, USA., Chandrasekaran P; Department of Biophysics, University of Texas Southwestern Medical Center, 6001 Forest Park Rd., Dallas, TX 75390-9041, USA., Williams NS; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9038, USA., Rosenbaum DM; Department of Biophysics, University of Texas Southwestern Medical Center, 6001 Forest Park Rd., Dallas, TX 75390-9041, USA. Electronic address: Dan.Rosenbaum@UTSouthwestern.edu., De Brabander JK; Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9038, USA. Electronic address: Jef.DeBrabander@UTSouthwestern.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2024 Feb 01; Vol. 99, pp. 129624. Date of Electronic Publication: 2024 Jan 23.
DOI: 10.1016/j.bmcl.2024.129624
Abstrakt: A structurally novel class of benzo- or pyrido-fused 1,3-dihydro-2H-imidazole-2-imines was designed and evaluated in an inositol phosphate accumulation assay for G q signaling to measure agonistic activation of the orexin receptor type 2 (OX 2 R). These compounds were synthesized in 4-9 steps overall from readily available starting materials. Analogs that contain a stereogenic methyl or cyclopropyl substituent at the benzylic center, and a correctly configured alkyl ether, alkoxyalkyl ether, cyanoalkyl ether, or α-hydroxyacetamido substituted homobenzylic sidechain were identified as the most potent activators of OX 2 R coupled G q signaling. Our results also indicate that agonistic activity was stereospecific at both the benzylic and homobenzylic stereogenic centra. We identified methoxyethoxy-substituted pyrido-fused dihydroimidazolimine analog 63c containing a stereogenic benzylic methyl group was the most potent agonist, registering a respectable EC 50 of 339 nM and a maximal response (E max ) of 96 % in this assay. In vivo pharmacokinetic analysis indicated good brain exposure for several analogs. Our combined results provide important information towards a structurally novel class of orexin receptor agonists distinct from current chemotypes.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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