Discovery of N-(4-methoxy-7-methylbenzo[d]thiazol-2-yl)isonicatinamide, ML293, as a novel, selective and brain penetrant positive allosteric modulator of the muscarinic 4 (M4) receptor

James M. Salovich, Paige N. Vinson, Douglas J. Sheffler, Atin Lamsal, Thomas J. Utley, Anna L. Blobaum, Thomas M. Bridges, Uyen Le, Carrie K. Jones, Michael R. Wood, J. Scott Daniels, P. Jeffrey Conn, Colleen M. Niswender, Craig W. Lindsley, Corey R. Hopkins

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Herein we describe the discovery and development of a novel class of M 4 positive allosteric modulators, culminating in the discovery of ML293. ML293 exhibited modest potency at the human M4 receptor (EC50 = 1.3 μM) and excellent efficacy as noted by the 14.6-fold leftward shift of the agonist concentration-response curve. ML293 was also selective versus the other muscarinic subtypes and displayed excellent in vivo PK properties in rat with low IV clearance (11.6 mL/min/kg) and excellent brain exposure (PO PBL, 10 mg/kg at 1 h, [Brain] = 10.3 μM, B:P = 0.85).

Original languageEnglish (US)
Pages (from-to)5084-5088
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume22
Issue number15
DOIs
StatePublished - Aug 1 2012

Keywords

  • CNS penetration
  • M
  • ML293
  • Muscarinic receptor 4
  • Positive allosteric modulator

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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    Salovich, J. M., Vinson, P. N., Sheffler, D. J., Lamsal, A., Utley, T. J., Blobaum, A. L., Bridges, T. M., Le, U., Jones, C. K., Wood, M. R., Scott Daniels, J., Jeffrey Conn, P., Niswender, C. M., Lindsley, C. W., & Hopkins, C. R. (2012). Discovery of N-(4-methoxy-7-methylbenzo[d]thiazol-2-yl)isonicatinamide, ML293, as a novel, selective and brain penetrant positive allosteric modulator of the muscarinic 4 (M4) receptor. Bioorganic and Medicinal Chemistry Letters, 22(15), 5084-5088. https://doi.org/10.1016/j.bmcl.2012.05.109