Compounds > cyclic(arg-gly-asp-d-phe-val)

cyclic(arg-gly-asp-d-phe-val) and naluzotan

cyclic(arg-gly-asp-d-phe-val) has been researched along with naluzotan* in 1 studies

Other Studies

1 other study(ies) available for cyclic(arg-gly-asp-d-phe-val) and naluzotan

Article	Year
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. Journal of medicinal chemistry, 2006, Jun-01, Volume: 49, Issue:11 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. Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; 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; Models, Molecular; Patch-Clamp Techniques; Piperazines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Serotonin 5-HT1 Receptor Agonists; Structure-Activity Relationship; Sulfonamides	2006

Article

Year

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.

Journal of medicinal chemistry, 2006, Jun-01, Volume: 49, Issue:11

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.

Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; 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; Models, Molecular; Patch-Clamp Techniques; Piperazines; Radioligand Assay; Rats; Rats, Sprague-Dawley; Serotonin 5-HT1 Receptor Agonists; Structure-Activity Relationship; Sulfonamides

2006