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.
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Authors | Oren 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 |
Journal | Journal of medicinal chemistry
(J Med Chem)
Vol. 49
Issue 11
Pg. 3116-35
(Jun 01 2006)
ISSN: 0022-2623 [Print] United States |
PMID | 16722631
(Publication Type: Journal Article)
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Chemical References |
- Anti-Anxiety Agents
- Antidepressive Agents
- Piperazines
- Serotonin 5-HT1 Receptor Agonists
- Sulfonamides
- naluzotan
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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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