Linked Life Data

16722631

Source:http://linkedlifedata.com/resource/pubmed/id/16722631

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
11
pubmed:dateCreated
2006-5-25
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
49
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3116-35
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:16722631-Animals, pubmed-meshheading:16722631-Anti-Anxiety Agents, pubmed-meshheading:16722631-Antidepressive Agents, pubmed-meshheading:16722631-Binding, Competitive, pubmed-meshheading:16722631-Biological Availability, pubmed-meshheading:16722631-Cell Line, pubmed-meshheading:16722631-Clinical Trials, Phase I as Topic, pubmed-meshheading:16722631-Dogs, pubmed-meshheading:16722631-Drug Design, pubmed-meshheading:16722631-Half-Life, pubmed-meshheading:16722631-Humans, pubmed-meshheading:16722631-Male, pubmed-meshheading:16722631-Mice, pubmed-meshheading:16722631-Microsomes, Liver, pubmed-meshheading:16722631-Models, Molecular, pubmed-meshheading:16722631-Patch-Clamp Techniques, pubmed-meshheading:16722631-Piperazines, pubmed-meshheading:16722631-Radioligand Assay, pubmed-meshheading:16722631-Rats, pubmed-meshheading:16722631-Rats, Sprague-Dawley, pubmed-meshheading:16722631-Serotonin 5-HT1 Receptor Agonists, pubmed-meshheading:16722631-Structure-Activity Relationship, pubmed-meshheading:16722631-Sulfonamides
pubmed:year
2006
pubmed:articleTitle
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.
pubmed:affiliation
Predix Pharmaceuticals Ltd., 3 Hayetzira Street, Ramat Gan 52521, Israel. becker@predixpharm.com
pubmed:publicationType
Journal Article, In Vitro