Discovery of a potent, dual serotonin and norepinephrine reuptake inhibitor.

The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior.

Dipeptidyl aspartyl fluoromethylketones as potent caspase inhibitors: peptidomimetic replacement of the P(2) amino acid by 2-aminoaryl acids and other non-natural amino acids.

As a continuation of our SAR studies of dipeptidyl aspartyl-fmk as caspase inhibitors, we explored the replacement of the P(2) amino acid by a 2-aminoaryl acid or other non-natural amino acids. Several of these compounds, such as 6l and 6p, were found to have good activities with inhibition potencies of around 100 nM in a caspase-3 enzyme assay. EP1113, Z-Val-(2-aminobenzoyl)-Asp-fmk (9b), is identified as a potent broad-spectrum caspase inhibitor with IC(50) values of 6-60 nM in different caspases.

Design, synthesis, structure-activity relationship, and in vivo activity of azabicyclic aryl amides as alpha7 nicotinic acetylcholine receptor agonists.

A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed alpha7 nAChR agonist, PNU-282,987, while maintaining the compound's other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987.

Discovery of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide, an agonist of the alpha7 nicotinic acetylcholine receptor, for the potential treatment of cognitive deficits in schizophrenia: synthesis and structure--activity relationship.

N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (14, PHA-543,613), a novel agonist of the alpha7 neuronal nicotinic acetylcholine receptor (alpha7 nAChR), has been identified as a potential treatment of cognitive deficits in schizophrenia.

Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 2. Structure-activity relationships of the 7- and 5-, 6-, 8-positions.

As a continuation of our efforts to discover and develop the apoptosis inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored the SAR of 4-aryl-4H-chromenes with modifications at the 7- and 5-, 6-, 8-positions. It was found that a small hydrophobic group, such as NMe2, NH2, NHEt, and OMe, is preferred at the 7-position. Di-substitution at either the 5,7-positions or the 6,7-positions generally led to a large decrease in potency.

Dipeptidyl aspartyl fluoromethylketones as potent caspase inhibitors: peptidomimetic replacement of the P2 alpha-amino acid by a alpha-hydroxy acid.

As a continuation of our SAR studies of dipeptidyl aspartyl-fmk as caspase inhibitors, we explored the replacement of the P2 alpha-amino acid by a peptidomimetic alpha-hydroxy acid. These alpha-carbamoyl-alkylcarbonyl-aspartyl fluoromethylketones were found to be potent caspase inhibitors, and the SAR of these compounds is similar to the corresponding dipeptidyl aspartyl-fmk. MX1153, (S)-3-methyl-2-(phenylcarbamoyl)butanoyl-Asp-fmk, is identified as a potent broad-spectrum caspase inhibitor, and is selective for caspases versus other proteases.

Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 1. Structure-activity relationships of the 4-aryl group.

By applying a novel cell- and caspase-based HTS assay, 2-amino-3-cyano-7-(dimethylamino)-4-(3-methoxy-4,5-methylenedioxyphenyl)-4H-chromene (1a) has been identified as a potent apoptosis inducer. Compound 1a was found to induce nuclear fragmentation and PARP cleavage, as well as to arrest cells at the G(2)/M stage and to induce apoptosis as determined by the flow cytometry analysis assay in multiple human cell lines (e.g.

Dipeptidyl aspartyl fluoromethylketones as potent caspase inhibitors: SAR of the N-protecting group.

This article describes the synthesis and biological evaluation of a group of N-protected Val-Asp-fmk as caspase inhibitors. The protecting group was found to contribute to caspase-3 inhibiting activity, and compounds with a large group such as Cbz are more active than compounds with a small group such as Ac. Compounds with more hydrophobic protecting groups were found to be more active in cell apoptosis protection assays, probably due to increased cell permeability.

Discovery of substituted N-phenyl nicotinamides as potent inducers of apoptosis using a cell- and caspase-based high throughput screening assay.

By applying a novel cell- and caspase-based HTS assay, a series of N-phenyl nicotinamides has been identified as a new class of potent inducers of apoptosis. Through SAR studies, a 20-fold increase in potency was achieved from a screening hit N-(4-methoxy-2-nitrophenyl)pyridine-3-carboxamide (1) to lead compound 6-methyl-N-(4-ethoxy-2-nitrophenyl)pyridine-3-carboxamide (10), with an EC(50) of 0.082 microM in the caspase activation assay in T47D breast cancer cells.