2. Academic Validation
  3. 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

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

Affiliation

  • 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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