Design and synthesis of N-[6-(Substituted Aminoethylideneamino)-2-Hydroxyindan-1-yl]arylamides as selective and potent muscarinic M₁ agonists.

Autor: Liu B; Lilly Research Laboratories, Indianapolis, IN 46285, United States. Electronic address: bfliu@lilly.com., Croy CH; Lilly Research Laboratories, Indianapolis, IN 46285, United States., Hitchcock SA; Lilly Research Laboratories, Indianapolis, IN 46285, United States., Allen JR; Lilly Research Laboratories, Indianapolis, IN 46285, United States., Rao Z; Lilly Research Laboratories, Indianapolis, IN 46285, United States., Evans D; Eli Lilly and Company, Windlesham, Surrey, UK., Bures MG; Lilly Research Laboratories, Indianapolis, IN 46285, United States., McKinzie DL; Lilly Research Laboratories, Indianapolis, IN 46285, United States., Watt ML; Lilly Research Laboratories, Indianapolis, IN 46285, United States., Stuart Gregory G; Lilly Research Laboratories, Indianapolis, IN 46285, United States., Hansen MM; Lilly Research Laboratories, Indianapolis, IN 46285, United States., Hoogestraat PJ; Lilly Research Laboratories, Indianapolis, IN 46285, United States., Jamison JA; Lilly Research Laboratories, Indianapolis, IN 46285, United States., Okha-Mokube FM; Lilly Research Laboratories, Indianapolis, IN 46285, United States., Stratford RE; Lilly Research Laboratories, Indianapolis, IN 46285, United States., Turner W; Lilly Research Laboratories, Indianapolis, IN 46285, United States., Bymaster F; Lilly Research Laboratories, Indianapolis, IN 46285, United States., Felder CC; Lilly Research Laboratories, Indianapolis, IN 46285, United States. Electronic address: felder_christan_c@lilly.com.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2015 Oct 01; Vol. 25 (19), pp. 4158-63. Date of Electronic Publication: 2015 Aug 08.
DOI: 10.1016/j.bmcl.2015.08.011
Abstrakt: The observation that cholinergic deafferentation of circuits projecting from forebrain basal nuclei to frontal and hippocampal circuits occurs in Alzheimer's disease has led to drug-targeting of muscarinic M1 receptors to alleviate cognitive symptoms. The high homology within the acetylcholine binding domain of this family however has made receptor-selective ligand development challenging. This work presents the synthesis scheme, pharmacokinetic and structure-activity-relationship study findings for M1-selective ligand, LY593093. Pharmacologically the compound acts as an orthosteric ligand. The homology modeling work presented however will illustrate that compound binding spans from the acetylcholine pocket to the extracellular loops of the receptor, a common allosteric vestibule for the muscarinic protein family. Altogether LY593093 represents a growing class of multi-topic ligands which interact with the receptors in both the ortho- and allosteric binding sites, but which exert their activation mechanism as an orthosteric ligand.
(Copyright © 2015. Published by Elsevier Ltd.)
Databáze: MEDLINE