Design, Synthesis, and Evaluation of Tetrasubstituted Pyridines as Potent 5-HT2C Receptor Agonists

  • ACS Med Chem Lett. 2015 Jan 20;6(3):329-33. doi: 10.1021/ml500507v.
Guy Rouquet  1 ,  Dianna E Moore  2 ,  Malcolm Spain  3 ,  Daniel M Allwood  1 ,  Claudio Battilocchio  1 ,  David C Blakemore  3 ,  Paul V Fish  3 ,  Stephen Jenkinson  4 ,  Alan S Jessiman  3 ,  Steven V Ley  1 ,  Gordon McMurray  3 ,  R Ian Storer  3
Affiliations
  • 1. Chemistry Department, University of Cambridge , Lensfield Road, Cambridge, CB2 1EW, U.K.
  • 2. Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Groton Laboratories , Eastern Point Road, Groton, Connecticut 06340, United States.
  • 3. Worldwide Medicinal Chemistry, and Discovery Biology, Pfizer Global Research and Development, Sandwich Laboratories , Sandwich, Kent CT13 9NJ, U.K.
  • 4. Global Safety Pharmacology, Pfizer Global Research and Development , 10646 Science Center Drive, San Diego, California 92121, United States.
PMID: 25815155 DOI: 10.1021/ml500507v
Abstract

A series of pyrido[3,4-d]azepines that are potent and selective 5-HT2C receptor agonists is disclosed. Compound 7 (PF-04781340) is identified as a suitable lead owing to good 5-HT2C potency, selectivity over 5-HT2B agonism, and in vitro ADME properties commensurate with an orally available and CNS penetrant profile. The synthesis of a novel bicyclic tetrasubstituted pyridine core template is outlined, including rationale to account for the unexpected formation of aminopyridine 13 resulting from an ammonia cascade cyclization.

Keywords
5-HT2C receptor agonist; CNS penetration; Tetrasubstituted pyridines; pyrido[3,4-d]azepine.
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