Synthesis and Pharmacological Characterization of 2-(2,6-Dichlorophenyl)-1-((1 S,3 R)-5-(3-hydroxy-3-methylbutyl)-3-(hydroxymethyl)-1-methyl-3,4-dihydroisoquinolin-2(1 H)-yl)ethan-1-one (LY3154207), a Potent, Subtype Selective, and Orally Available Positive Allosteric Modulator of the Human Dopamine D1 Receptor

  • J Med Chem. 2019 Oct 10;62(19):8711-8732. doi: 10.1021/acs.jmedchem.9b01234.
Junliang Hao ,  James P Beck ,  John M Schaus ,  Joseph H Krushinski ,  Qi Chen ,  Christopher D Beadle ,  Paloma Vidal ,  Matthew R Reinhard ,  Bruce A Dressman ,  Steven M Massey ,  Serge L Boulet ,  Michael P Cohen ,  Brian M Watson ,  David Tupper ,  Kevin M Gardinier ,  Jason Myers ,  Anette M Johansson ,  Jeffery Richardson ,  Daniel S Richards  1 ,  Erik J Hembre ,  David M Remick ,  David A Coates ,  Rajni M Bhardwaj ,  Benjamin A Diseroad ,  David Bender ,  Greg Stephenson ,  Craig D Wolfangel ,  Nuria Diaz ,  Brian G Getman ,  Xu-Shan Wang ,  Beverly A Heinz ,  Jeff W Cramer ,  Xin Zhou ,  Deanna L Maren ,  Julie F Falcone ,  Rebecca A Wright ,  Stephen N Mitchell ,  Guy Carter ,  Charles R Yang ,  Robert F Bruns ,  Kjell A Svensson
Affiliations
  • 1. AMRI UK Ltd , Erl Wood Manor, Sunninghill Road , Windlesham , Surrey , GU20 6PH , United Kingdom.
PMID: 31532644 DOI: 10.1021/acs.jmedchem.9b01234
Abstract

Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 (3) as a novel, potent, and subtype selective human D1 positive allosteric modulator (PAM) with minimal allosteric agonist activity. Conformational studies showed LY3154207 adopts an unusual boat conformation, and a binding pose with the human D1 receptor was proposed based on this observation. In contrast to orthosteric agonists, LY3154207 showed a distinct pharmacological profile without a bell-shaped dose-response relationship or tachyphylaxis in preclinical models. Identification of a crystalline form of free LY3154207 from the discovery lots was not successful. Instead, a novel cocrystal form with superior solubility was discovered and determined to be suitable for development. This cocrystal form was advanced to clinical development as a potential first-in-class D1 PAM and is now in phase 2 studies for Lewy body dementia.

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