Identification of 5-(1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)thiophene-2-Carboxamides as Novel and Selective Monoamine Oxidase B Inhibitors Used to Improve Memory and Cognition

ACS Chem Neurosci. 2017 Dec 20;8(12):2746-2758. doi: 10.1021/acschemneuro.7b00282. Epub 2017 Sep 20.

Abstract

Initial work in Drosophila and mice demonstrated that the transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) is a master control gene for memory formation. The relationship between CREB and memory has also been found to be true in other species, including aplysia and rats. It is thus well-established that CREB activation plays a central role in memory enhancement and that CREB is activated during memory formation. On the basis of these findings, a phenotypic high-throughput screening campaign utilizing a CRE-luciferase (CRE-Luci) SK-N-MC cell line was performed to identify compounds that enhance transcriptional activation of the CRE promoter with a suboptimal dose of forskolin. A number of small-molecule hits of unknown mechanisms of action were identified in the screening campaign, including HT-0411. Follow-up studies suggested that the CREB activation by HT-0411 is attributed to its specific and selective inhibition of monoamine oxidase B (MAO-B). Further, HT-0411 was shown to improve 24 h memory in rodents in a contextual fear conditioning model. This report describes the lead optimization of a series of 5-(1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl) thiophene-2-carboxamides that were identified as novel, potent, and selective inhibitors of MAO-B. Extensive SAR studies and in vivo behavioral evaluations of this and other related analogue series identified a number of potential clinical development candidates; ultimately, compound 8f was identified as a candidate molecule with high selectivity toward MAO-B (29-56 nM) over MAO-A (19% inhibition at a screening concentration of 50 μM), an excellent profile against a panel of other enzymes and receptors, good pharmacokinetic properties in rodents and dogs, and efficacy in multiple rodent memory models.

Keywords: CREB activation; MAO-B inhibitors; long-term memory; phenotypic screening; synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / administration & dosage
  • Amides / chemistry
  • Animals
  • Carboxylic Acids / administration & dosage*
  • Carboxylic Acids / chemistry*
  • Cognition / drug effects*
  • Cognition / physiology
  • Dose-Response Relationship, Drug
  • Male
  • Memory / drug effects*
  • Memory / physiology
  • Mice, Inbred C57BL
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / administration & dosage
  • Monoamine Oxidase Inhibitors / chemistry
  • Nootropic Agents / administration & dosage*
  • Nootropic Agents / chemistry*
  • Rats
  • Treatment Outcome

Substances

  • Amides
  • Carboxylic Acids
  • Monoamine Oxidase Inhibitors
  • Nootropic Agents
  • Monoamine Oxidase