Discovery of Tricyclic Triazolo- and Imidazopyridine Lactams as M 1 Positive Allosteric Modulators

Julie L. Engers, Aaron M. Bender, Jacob J. Kalbfleisch, Hyekyung P. Cho, Kaelyn S. Lingenfelter, Vincent B. Luscombe, Changho Han, Bruce J. Melancon, Anna L. Blobaum, Jonathan W. Dickerson, Jerri M. Rook, Colleen M. Niswender, Kyle A. Emmitte, P. Jeffrey Conn, Craig W. Lindsley

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

This Letter describes the chemical optimization of a new series of muscarinic acetylcholine receptor subtype 1 (M 1 ) positive allosteric modulators (PAMs) based on novel tricyclic triazolo- and imidazopyridine lactam cores, devoid of M 1 agonism, e.g., no M 1 ago-PAM activity, in high expressing recombinant cell lines. While all the new tricyclic congeners afforded excellent rat pharmacokinetic (PK) properties (CL p < 8 mL/min/kg and t 1/2 > 5 h), regioisomeric triazolopyridine analogues were uniformly not CNS penetrant (K p < 0.05), despite a lack of hydrogen bond donors. However, removal of a single nitrogen atom to afford imidazopyridine derivatives proved to retain the excellent rat PK and provide high CNS penetration (K p > 2), despite inclusion of a basic nitrogen. Moreover, 24c was devoid of M 1 agonism in high expressing recombinant cell lines and did not induce cholinergic seizures in vivo in mice. Interestingly, all of the new M 1 PAMs across the diverse tricyclic heterocyclic cores possessed equivalent CNS MPO scores (>4.5), highlighting the value of both "medicinal chemist's eye" and experimental data, e.g., not sole reliance (or decision bias) on in silico calculated properties, for parameters as complex as CNS penetration.

Original languageEnglish
Pages (from-to)1035-1042
Number of pages8
JournalACS Chemical Neuroscience
Volume10
Issue number3
DOIs
StatePublished - 20 Mar 2019

Keywords

  • CNS
  • M
  • PAM
  • Positive allosteric modulator
  • SAR
  • muscarinic acetylcholine receptor 1

Fingerprint Dive into the research topics of 'Discovery of Tricyclic Triazolo- and Imidazopyridine Lactams as M <sub>1</sub> Positive Allosteric Modulators'. Together they form a unique fingerprint.

  • Cite this

    Engers, J. L., Bender, A. M., Kalbfleisch, J. J., Cho, H. P., Lingenfelter, K. S., Luscombe, V. B., Han, C., Melancon, B. J., Blobaum, A. L., Dickerson, J. W., Rook, J. M., Niswender, C. M., Emmitte, K. A., Conn, P. J., & Lindsley, C. W. (2019). Discovery of Tricyclic Triazolo- and Imidazopyridine Lactams as M 1 Positive Allosteric Modulators ACS Chemical Neuroscience, 10(3), 1035-1042. https://doi.org/10.1021/acschemneuro.8b00311