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

被引:116
作者
Becker, Oren M.
Dhanoa, Dale S.
Marantz, Yael
Chen, Dongli
Shacham, Sharon
Cheruku, Srinivasa
Heifetz, Alexander
Mohanty, Pradyumna
Fichman, Merav
Sharadendu, Anurag
Nudelman, Raphael
Kauffman, Michael
Noiman, Silvia
机构
[1] Predix Pharmaceut Ltd, IL-52521 Ramat Gan, Israel
[2] Predix Pharmaceut Inc, Lexington, MA 02421 USA
关键词
D O I
10.1021/jm0508641
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 alpha(1)-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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页码:3116 / 3135
页数:20
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