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An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression.

Abstract
We report the discovery of a novel, potent, and selective amidosulfonamide nonazapirone 5-HT1A agonist for the treatment of anxiety and depression, which is now in Phase III clinical trials for generalized anxiety disorder (GAD). The discovery of 20m (PRX-00023), N-{3-[4-(4-cyclohexylmethanesulfonylaminobutyl)piperazin-1-yl]phenyl}acetamide, and its backup compounds, followed a new paradigm, driving the entire discovery process with in silico methods and seamlessly integrating computational chemistry with medicinal chemistry, which led to a very rapid discovery timeline. The program reached clinical trials within less than 2 years from initiation, spending less than 6 months in lead optimization with only 31 compounds synthesized. In this paper we detail the entire discovery process, which started with modeling the 3D structure of 5-HT1A using the PREDICT methodology, and then performing in silico screening on that structure leading to the discovery of a 1 nM lead compound (8). The lead compound was optimized following a strategy devised based on in silico 3D models and realized through an in silico-driven optimization process, rapidly overcoming selectivity issues (affinity to 5-HT1A vs alpha1-adrenergic receptor) and potential cardiovascular issues (hERG binding), leading to a clinical compound. Finally we report key in vivo preclinical and Phase I clinical data for 20m tolerability, pharmacokinetics, and pharmacodynamics and show that these favorable results are a direct outcome of the properties that were ascribed to the compound during the rational structure-based discovery process. We believe that this is one of the first examples for a Phase III drug candidate that was discovered and optimized, from start to finish, using in silico model-based methods as the primary tool.
AuthorsOren M Becker, Dale S Dhanoa, Yael Marantz, Dongli Chen, Sharon Shacham, Srinivasa Cheruku, Alexander Heifetz, Pradyumna Mohanty, Merav Fichman, Anurag Sharadendu, Raphael Nudelman, Michael Kauffman, Silvia Noiman
JournalJournal of medicinal chemistry (J Med Chem) Vol. 49 Issue 11 Pg. 3116-35 (Jun 01 2006) ISSN: 0022-2623 [Print] United States
PMID16722631 (Publication Type: Journal Article)
Chemical References
  • Anti-Anxiety Agents
  • Antidepressive Agents
  • Piperazines
  • Serotonin 5-HT1 Receptor Agonists
  • Sulfonamides
  • naluzotan
Topics
  • Animals
  • Anti-Anxiety Agents (chemical synthesis, chemistry, pharmacology)
  • Antidepressive Agents (chemical synthesis, chemistry, pharmacology)
  • Binding, Competitive
  • Biological Availability
  • Cell Line
  • Clinical Trials, Phase I as Topic
  • Dogs
  • Drug Design
  • Half-Life
  • Humans
  • In Vitro Techniques
  • Male
  • Mice
  • Microsomes, Liver (metabolism)
  • Models, Molecular
  • Patch-Clamp Techniques
  • Piperazines (chemical synthesis, chemistry, pharmacology)
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin 5-HT1 Receptor Agonists
  • Structure-Activity Relationship
  • Sulfonamides (chemical synthesis, chemistry, pharmacology)

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