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.

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.

Synthesis and insecticidal activity of fluorinated 2-(2,6-dichloro-4-trifluoromethylphenyl)-2,4,5,6-tetrahydrocyclopentapyrazoles.

A number of fluorinated 1-aryl-tetrahydrocyclopentapyrazoles were synthesized and their insecticidal activity was evaluated. Some of the fluorinated compounds had significant insecticidal properties.

Synthesis and GABA receptor potency of 3-thiomethyl-4-(hetero)aryl-5-amino-1-phenylpyrazoles.

A convenient synthetic route to novel 4-arylpyrazoles is described. The potential for insecticidal activity through GABA channel blockage by this series of compounds, as well as their selectivity for insect versus mammalian receptors, are explored through in vitro and in vivo assays.

5-amino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-[3H3]-methylsulfanyl-1H-pyrazole-4-carbonitrile (CTOM): synthesis and characterization of a novel and selective insect GABA receptor radioligand.

Pyrazole 2a is a novel, potent ligand for insect GABA receptors obtained from housefly head membrane preparations (K(i)=8 nM). It is 500-fold selective against the mammalian receptor (mouse brain preparations). Its specifically tritiated version (2b) was synthesized by reduction of disulfide 10 with NaBH(4) followed by alkylation with [3H(3)]-CH(3)I.

Discovery of potent and selective small molecule NPY Y5 receptor antagonists.

The discovery of a new class of sulfonamide NPY Y5 receptor antagonists is described. Optimization of this series led to the identification of compounds with high affinity for the hY5 subtype and excellent selectivity over the other NPY receptor subtypes. The SAR for this series was examined and a model for understanding the ligand-receptor interactions was developed.