2. Academic Validation
  3. Design, Synthesis, and Evaluation of Tetrasubstituted Pyridines as Potent 5-HT2C Receptor Agonists

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

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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