title: 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.
authors.affiliation: Predix Pharmaceuticals Ltd., 3 Hayetzira Street, Ramat Gan 52521, Israel. becker@predixpharm.com
authors.forename: Oren M
authors.initials: OM
authors.lastname: Becker
authors.forename: Dale S
authors.initials: DS
authors.lastname: Dhanoa
authors.forename: Yael
authors.initials: Y
authors.lastname: Marantz
authors.forename: Dongli
authors.initials: D
authors.lastname: Chen
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Cheruku
authors.forename: Alexander
authors.initials: A
authors.lastname: Heifetz
authors.forename: Pradyumna
authors.initials: P
authors.lastname: Mohanty
authors.forename: Merav
authors.initials: M
authors.lastname: Fichman
authors.forename: Anurag
authors.initials: A
authors.lastname: Sharadendu
authors.forename: Raphael
authors.initials: R
authors.lastname: Nudelman
authors.forename: Michael
authors.initials: M
authors.lastname: Kauffman
authors.forename: Silvia
authors.initials: S
authors.lastname: Noiman
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001667:Binding, Competitive; D001682:Biological Availability; D002460:Cell Line; D017321:Clinical Trials, Phase I as Topic; D004285:Dogs; D015195:Drug Design; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D058825:Serotonin 5-HT1 Receptor Agonists; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D010879:Piperazines; D058825:Serotonin 5-HT1 Receptor Agonists; D013449:Sulfonamides; C511631:naluzotan