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We prepared a series of quinoxalin-2-mercapto-acetyl-urea analogs and evaluated them for their ability to inhibit viral egress in our Marburg and Ebola VP40 VLP budding assays in HEK293T cells. We also evaluated selected compounds in our bimolecular complementation assay (BiMC) to detect and visualize a Marburg mVP40-Nedd4 interaction in live mammalian cells. Antiviral activity was assessed for selected compounds using a live recombinant vesicular stomatitis virus (VSV) (M40 virus) that expresses the EBOV VP40 PPxY L-domain. Finally selected compounds were evaluated in several ADME assays to have an early assessment of their drug properties. Our compounds had low nM potency in these assays (e.g., compounds 21, 24, 26, 39), and had good human liver microsome stability, as well as little or no inhibition of P450 3A4.

Small molecule (1) has been identified as a selective partial agonist of Opioid Receptor Like-1 (ORL-1) with potential utility for the treatment of anxiety and other disorders. Nociceptin (orphanin FQ) is an endogenous peptide ligand that binds to ORL-1, however it does not bind the classical δ, μ and κ opioid receptors with high affinity. The synthesis of 1 involved using a molecular diversity approach, to rapidly advance a library of compounds for biological testing. A lead selective potent partial agonist (35-fold ORL-1/Mu) progressed to ORL-1 (NOP or OP4) proof of concept testing in advanced studies. The synthetic approach and biological data for the related chemical series will be presented.

We designed a series of anilino-indoylmaleimides based on structural elements from literature JAK3 inhibitors 3 and 4, and our lead 5. These new compounds were tested as inhibitors of JAKs 1, 2 and 3 and TYK2 for therapeutic intervention in rheumatoid arthritis (RA). Our requirements, based on current scientific rationale for optimum efficacy against RA with reduced side effects, was for potent, mixed JAK1 and 3 inhibition, and selectivity over JAK2. Our efforts yielded a potent JAK3 inhibitor 11d and its eutomer 11e. These compounds were highly selective for inhibition of JAK3 over JAK2 and TYK. The compounds displayed only modest JAK1 inhibition.

Botulinum neurotoxins (BoNTs) are the most toxic proteins known to man, exposure to which results in flaccid paralysis. Given their extreme potency, these proteins have become studied as possible weapons of bioterrorism; however, effective treatments that function after intoxication have not progressed to the clinic. Here, we have reexamined one of the most effective inhibitors, 2,4-dichlorocinnamyl hydroxamate, in the context of the known plasticity of the BoNT/A light chain metalloprotease. Our studies have shown that modifications of this compound are tolerated and result in improved inhibitors, with the best compound having an IC50 of 0.23 μM. Given the inconsistency of structure–activity relationship trends observed across similar compounds, this data argues for caution in extrapolating across structural series

A series of pyrido[1,2- a ]benzimidazoles (PBIs) with substitution on the N 5 -nitrogen has been synthesized and found to possess high affinity for the benzodiazepine (BZD) site on the GABA-A receptor. The compounds evaluated include those bearing a heteroalkyl group and heterocyclic rings. The most promising of these compounds is ethoxymethyl analogue 24 , which has an IC 50 of 0.1 nM for the BZD site on the GABA-A receptor and has been advanced to human clinical trials.

1,3-Disubstituted-5-aminopyrazoles were prepared based on a lead compound found through high-throughput screening of our corporate compound library in an assay measuring affinity for the human neuropeptide Y5 receptor. The target compounds were prepared by cyclization of alpha-cyanoketones with appropriate hydrazines, followed by reduction and coupling to various sulfonamido-carboxylic acids. Several of these arylpyrazoles (e.g., 19 and 45) displayed high affinity for the human NPY Y5 receptor (20nM IC(50)s).

A variety of pyrido[1,2-a]benzimidazoles (PBIs) modified on the A-ring were prepared and evaluated for affinity to the benzodiazepine binding site on the GABA-A receptor and in animal models predictive of anxiolytic activity in humans. A-ring benzo-fused derivative 7 exhibited potent activity, as did the 6- and 7-pyrido compounds 3 and 4.

Several of the key metabolites of mazapertine, a novel antipyschotic agent, were prepared in order to firmly establish their chemical structure and to obtain samples for biological testing. Hydroxymazapertine 3 was synthesized via a multi-step procedure starting from 5-fluoro-2-nitrophenol (8). Alcohol 4 was originally proposed for one of the major metabolites, but the confirmed structure after synthesis was isomer 20.

Hindered rotation analogs of the antipsychotic mazapertine (1) were prepared. These compounds exhibited high affinity for the HT-1A receptor, but not for other serotonin or dopamine receptors. The related β-carboline structures were also sybthetized and were found to be potent 5-HT1A ligands.

The major human metabolite of atomoxetine (4-hydroxyatomoxetine) was tested against a panel of receptors and enzymes, and was found to interact with the mu, delta, and kappa-opioid receptors based upon studies involving both binding and functional assays. 4-hydroxyatomoxetine was determined to be a partial agonist of the kappa-opioid receptor.

Piperazinyl benzamidines were prepared and found to bind to the rat delta (δ) opioid receptor. The most active compounds had a N,N -diethylcarboxamido group and a N -benzyl piperazine. The most potent among these was N,N -diethyl-4-[4-(phenylmethyl)-1-piperazinyl][2-(trifluoromethyl)phenyl]iminomethyl]benzamide ( 27 ) with a 1.22 nM K i for the rat δ opioid receptor and ca. 1000× selectivity relative to the μ opioid subtype.

The synthesis of 1-deoxymannojirimycin ( 1 ) is readily achieved in four steps from 1-methyl-2,3-isopropylidene- d -mannofuranoside ( 2 ). The key step is a double reductive amination of 5-keto- d -mannose ( 3 ) using NaBH 3 CN, entailing a marked divergence in stereocontrol relative to the reported use of catalytic methods. The important enzyme inhibitor 1-deoxymannojirimycin ( 1 ) was prepared from 5-keto- D -mannose ( 3 ) in two steps. The key double reductive amination displays a marked divergence in stereocontrol relative to that reported for similar reactions performed under catalytic conditions.