Optimization of a series of heterocycles as survival motor neuron gene transcription enhancers

Sungwoon Choi, Alyssa N. Calder, Eliza H. Miller, Kierstyn P. Anderson, Dawid K. Fiejtek, Anne Rietz, Hongxia Li, Jonathan J. Cherry, Kevin M. Quist, Xuechao Xing, Marcie A. Glicksman, Gregory D. Cuny, Christian L. Lorson, Elliot Androphy, Kevin J. Hodgetts

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Spinal muscular atrophy (SMA) is a neurodegenerative disorder that results from mutations in the SMN1 gene, leading to survival motor neuron (SMN) protein deficiency. One therapeutic strategy for SMA is to identify compounds that enhance the expression of the SMN2 gene, which normally only is a minor contributor to functional SMN protein production, but which is unaffected in SMA. A recent high-throughput screening campaign identified a 3,4-dihydro-4-phenyl-2(1H)-quinolinone derivative (2) that increases the expression of SMN2 by 2-fold with an EC50 = 8.3 µM. A structure-activity relationship (SAR) study revealed that the array of tolerated substituents, on either the benzo portion of the quinolinone or the 4-phenyl, was very narrow. However, the lactam ring of the quinolinone was more amenable to modifications. For example, the quinazolinone (9a) and the benzoxazepin-2(3H)-one (19) demonstrated improved potency and efficacy for increase in SMN2 expression as compared to 2.

Original languageEnglish (US)
Pages (from-to)5144-5148
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number23
DOIs
StatePublished - Dec 1 2017

Fingerprint

Spinal Muscular Atrophy
Quinolones
Motor Neurons
Transcription
Neurons
Genes
Quinazolinones
4-Quinolones
Lactams
Protein Deficiency
Structure-Activity Relationship
Neurodegenerative Diseases
Screening
Proteins
Throughput
Derivatives
Gene Expression
Mutation
Therapeutics

Keywords

  • Spinal muscular atrophy
  • Survival motor neuron

ASJC Scopus subject areas

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

Cite this

Choi, S., Calder, A. N., Miller, E. H., Anderson, K. P., Fiejtek, D. K., Rietz, A., ... Hodgetts, K. J. (2017). Optimization of a series of heterocycles as survival motor neuron gene transcription enhancers. Bioorganic and Medicinal Chemistry Letters, 27(23), 5144-5148. https://doi.org/10.1016/j.bmcl.2017.10.066

Optimization of a series of heterocycles as survival motor neuron gene transcription enhancers. / Choi, Sungwoon; Calder, Alyssa N.; Miller, Eliza H.; Anderson, Kierstyn P.; Fiejtek, Dawid K.; Rietz, Anne; Li, Hongxia; Cherry, Jonathan J.; Quist, Kevin M.; Xing, Xuechao; Glicksman, Marcie A.; Cuny, Gregory D.; Lorson, Christian L.; Androphy, Elliot; Hodgetts, Kevin J.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 27, No. 23, 01.12.2017, p. 5144-5148.

Research output: Contribution to journalArticle

Choi, S, Calder, AN, Miller, EH, Anderson, KP, Fiejtek, DK, Rietz, A, Li, H, Cherry, JJ, Quist, KM, Xing, X, Glicksman, MA, Cuny, GD, Lorson, CL, Androphy, E & Hodgetts, KJ 2017, 'Optimization of a series of heterocycles as survival motor neuron gene transcription enhancers', Bioorganic and Medicinal Chemistry Letters, vol. 27, no. 23, pp. 5144-5148. https://doi.org/10.1016/j.bmcl.2017.10.066
Choi, Sungwoon ; Calder, Alyssa N. ; Miller, Eliza H. ; Anderson, Kierstyn P. ; Fiejtek, Dawid K. ; Rietz, Anne ; Li, Hongxia ; Cherry, Jonathan J. ; Quist, Kevin M. ; Xing, Xuechao ; Glicksman, Marcie A. ; Cuny, Gregory D. ; Lorson, Christian L. ; Androphy, Elliot ; Hodgetts, Kevin J. / Optimization of a series of heterocycles as survival motor neuron gene transcription enhancers. In: Bioorganic and Medicinal Chemistry Letters. 2017 ; Vol. 27, No. 23. pp. 5144-5148.
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