2. Academic Validation
  3. Design and Identification of a Novel, Functionally Subtype Selective GABAA Positive Allosteric Modulator (PF-06372865)

Design and Identification of a Novel, Functionally Subtype Selective GABAA Positive Allosteric Modulator (PF-06372865)

  • J Med Chem. 2019 Jun 27;62(12):5773-5796. doi: 10.1021/acs.jmedchem.9b00322.
Robert M Owen,  David Blakemore,  Lishuang Cao,  Neil Flanagan,  Rebecca Fish,  Karl R Gibson 1,  Rachel Gurrell,  Chan Woo Huh 2,  Juha Kammonen,  Elisabeth Mortimer-Cassen,  Sarah A Nickolls,  Kiyoyuki Omoto,  Dafydd Owen 2,  Andy Pike,  David C Pryde,  David S Reynolds,  Rosemarie Roeloffs 3,  Colin Rose 2,  Clara Stead,  Mifune Takeuchi 1,  Joseph S Warmus 2,  Christine Watson 1
Affiliations

Affiliations

  • 1 Worldwide Medicinal Chemistry Sandwich Laboratories , Pfizer Global Research and Development , Ramsgate Road , Sandwich , Kent CT13 9NJ , United Kingdom.
  • 2 Worldwide Medicinal Chemistry , Pfizer Global Research & Development , 558 Eastern Point Road , Groton , Connecticut 06340 , United States.
  • 3 Pfizer Icagen , Research Triangle Park , North Carolina 27703 , United States.
PMID: 30964988 DOI: 10.1021/acs.jmedchem.9b00322
Abstract

The design, optimization, and evaluation of a series of novel imidazopyridazine-based subtype-selective positive allosteric modulators (PAMs) for the GABAA ligand-gated ion channel are described. From a set of initial hits multiple subseries were designed and evaluated based on binding affinity and functional activity. As designing in the desired level of functional selectivity proved difficult, a probability-based assessment was performed to focus the project's efforts on a single subseries that had the greatest odds of delivering the target profile. These efforts ultimately led to the identification of two precandidates from this subseries, which were advanced to preclinical safety studies and subsequently to the identification of the clinical candidate PF-06372865.

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