Identification of a Novel Polyamine Scaffold With Potent Efflux Pump Inhibition Activity Toward Multi-Drug Resistant Bacterial Pathogens.

We have previously reported the use of combinatorial chemistry to identify broad-spectrum antibacterial agents. Herein, we extend our analysis of this technology toward the discovery of anti-resistance molecules, focusing on efflux pump inhibitors. Using high-throughput screening against multi-drug resistant , we identified a polyamine scaffold that demonstrated strong efflux pump inhibition without possessing antibacterial effects.

Differential regulation of alcohol taking and seeking by antagonism at α4β2 and α3β4 nAChRs.

Rationale: Alcoholism is a serious public health problem throughout the world. Current pharmacotherapies for the treatment of this disorder are poorly effective. Preclinical and clinical findings point to nicotinic acetylcholine receptors (nAChRs) as a promising target for the development of novel and effective medications.

Highly Selective and Potent α4β2 nAChR Antagonist Inhibits Nicotine Self-Administration and Reinstatement in Rats.

The α4β2 nAChR is the most predominant subtype in the brain and is a well-known culprit for nicotine addiction. Previously we presented a series of α4β2 nAChR selective compounds that were discovered from a mixture-based positional-scanning combinatorial library. Here we report further optimization identified highly potent and selective α4β2 nAChR antagonists 5 (AP-202) and 13 (AP-211).

Combinatorial Libraries As a Tool for the Discovery of Novel, Broad-Spectrum Antibacterial Agents Targeting the ESKAPE Pathogens.

Mixture based synthetic combinatorial libraries offer a tremendous enhancement for the rate of drug discovery, allowing the activity of millions of compounds to be assessed through the testing of exponentially fewer samples. In this study, we used a scaffold-ranking library to screen 37 different libraries for antibacterial activity against the ESKAPE pathogens. Each library contained between 10000 and 750000 structural analogues for a total of >6 million compounds.

Scaffold ranking and positional scanning utilized in the discovery of nAChR-selective compounds suitable for optimization studies.

Nicotine binds to nicotinic acetylcholine receptors (nAChR), which can exist as many different subtypes. The α4β2 nAChR is the most prevalent subtype in the brain and possesses the most evidence linking it to nicotine seeking behavior. Herein we report the use of mixture based combinatorial libraries for the rapid discovery of a series of α4β2 nAChR selective compounds.

Shifting from the single to the multitarget paradigm in drug discovery.

Increasing evidence that several drug compounds exert their effects through interactions with multiple targets is boosting the development of research fields that challenge the data reductionism approach. In this article, we review and discuss the concepts of drug repurposing, polypharmacology, chemogenomics, phenotypic screening and high-throughput in vivo testing of mixture-based libraries in an integrated manner. These research fields offer alternatives to the current paradigm of drug discovery, from a one target-one drug model to a multiple-target approach.

A small molecule inhibitor of the Wnt antagonist secreted frizzled-related protein-1 stimulates bone formation.

Canonical Wnt signaling has been demonstrated to increase bone formation, and Wnt pathway components are being pursued as potential drug targets for osteoporosis and other metabolic bone diseases. Deletion of the Wnt antagonist secreted frizzled-related protein (sFRP)-1 in mice activates canonical signaling in bone and increases trabecular bone formation in aged animals. We have developed small molecules that bind to and inhibit sFRP-1 in vitro and demonstrate robust anabolic activity in an ex vivo organ culture assay.

Modulation of Wnt signaling through inhibition of secreted frizzled-related protein I (sFRP-1) with N-substituted piperidinyl diphenylsulfonyl sulfonamides.

The diphenylsulfonyl sulfonamide scaffold represented by 1 (WAY-316606) are small molecule inhibitors of the secreted protein sFRP-1, an endogenous antagonist of the secreted glycoprotein Wnt. Modulators of the Wnt pathway have been proposed as anabolic agents for the treatment of osteoporosis or other bone-related disorders. Details of the structure-activity relationships and biological activity from the first structural class of this scaffold will be discussed.

Cycloalkyl[b][1,4]benzodiazepinoindoles are agonists at the human 5-HT2C receptor.

Evaluation of selected compounds from our Corporate Compound Library in a human 5-HT(2C) receptor binding assay led to the discovery of WAY-629, a cyclohexyl[b][1,4]benzodiazepinoindole (K(i) 56 nM, E(max) 90%), which is selective for the 5-HT(2C) receptor versus other serotonin receptor subtypes, and dopamine, histamine, adrenergic, and muscarinic receptors. In addition, WAY-629 was active in vivo in a rat model of feeding behavior. An SAR study based on WAY-629 led to compound 11 (K(i) 13 nM, E(max) 102%).