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Design, Synthesis, and Biological Evaluation of Novel, Non-Brain-Penetrant, Hybrid Cannabinoid CB1R Inverse Agonist/Inducible Nitric Oxide Synthase (iNOS) Inhibitors for the Treatment of Liver Fibrosis.

Malliga R IyerResat CinarAlexis KatzMichael GaoKatalin ErdelyiTony JourdanNathan J CoffeyPal PacherGeorge Kunos
Published in: Journal of medicinal chemistry (2017)
We report the design, synthesis, and structure-activity relationships of novel dual-target compounds with antagonist/inverse agonist activity at cannabinoid receptor type 1 (CB1R) and inhibitory effect on inducible nitric oxide synthase (iNOS). A series of 3,4-diarylpyrazolinecarboximidamides were synthesized and evaluated in CB1 receptor (CB1R) binding assays and iNOS activity assays. The novel compounds, designed to have limited brain penetrance, elicited potent in vitro CB1R antagonist activities and iNOS inhibitory activities. Some key compounds displayed high CB1R binding affinities. Compound 7 demonstrated potent in vivo pharmacological activities such as reduction of food intake mediated by the antagonism of the CB1Rs and antifibrotic effect in the animal models of fibrosis mediated by iNOS inhibition and CB1R antagonism.
Keyphrases
  • nitric oxide synthase
  • nitric oxide
  • liver fibrosis
  • high throughput
  • white matter
  • binding protein
  • transcription factor
  • resting state
  • brain injury
  • dna binding
  • blood brain barrier
  • combination therapy
  • smoking cessation