Matcher: An Open-Source Application for Translating Large Structure/Property Data Sets into Insights for Drug Design.

To solve recurring problems in drug discovery, matched molecular pair (MMP) analysis is used to understand relationships between chemical structure and function. For the MMP analysis of large data sets (>10,000 compounds), available tools lack flexible search and visualization functionality and require computational expertise. Here, we present Matcher, an open-source application for MMP analysis, with novel search algorithms and fully automated querying-to-visualization that requires no programming expertise.

Phe19 modification of HDM2-p53 PPI inhibitors to alleviate CYP3A4 metabolism/mechanism-based inhibition liability.

The discovery of potent, bioavailable small molecule inhibitors of p53-HDM2 PPI led us to investigate subsequent modifications to address a CYP3A4 time-dependent inhibition liability. On the basis of the crystal structure of HDM2 in complex with 2, further functionalization of the solvent exposed area of the molecule that binds to Phe19 pocket were investigated as a strategy to modulate the molecule liphophilicity. Introduction of 2-oxo-nicotinic amide at Phe19 proved a viable strategy in obtaining inhibitors exempt from CYP3A4 time-dependent inhibition liability.

Diversity & tractability revisited in collaborative small molecule phenotypic screening library design.

Identification of purposeful chemical matter on a broad range of drug targets is of high importance to the pharmaceutical industry. However, disease-relevant but more complex hit-finding plans require flexibility regarding the subset of the compounds that we screen. Herein we describe a strategy to design high-quality small molecule screening subsets of two different sizes to cope with a rapidly changing early discovery portfolio.

Strategy for Extending Half-life in Drug Design and Its Significance.

Preclinical optimization of compounds toward viable drug candidates requires an integrated understanding of properties that impact predictions of the clinically efficacious dose. The importance of optimizing half-life, unbound clearance, and potency and how they impact dose predictions are discussed in this letter. Modest half-life improvements for short half-life compounds can dramatically lower the efficacious dose.

Structure-activity relationship study of 4-substituted piperidines at Leu26 moiety of novel p53-hDM2 inhibitors.

Led by the structural information of the screening hit with mDM2 protein, a structure modification of Leu26 moiety of the novel p53-hDM2 inhibitors was conducted. A structure-activity relationship study of 4-substituted piperidines revealed compound 20t with good potencies and excellent CYP450 profiles.

Discovery of Novel 3,3-Disubstituted Piperidines as Orally Bioavailable, Potent, and Efficacious HDM2-p53 Inhibitors.

A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by 21 has been developed from the initial lead 1. Research focused on optimization of a crucial HDM2 Trp23-ligand interaction led to the identification of 2-(trifluoromethyl)thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice.

Pivotal Role of an Aliphatic Side Chain in the Development of an HDM2 Inhibitor.

Introduction of an aliphatic side chain to a key position of a novel piperidine-based HDM2 inhibitor scaffold resulted in significant potency gains, enabling further series progression.

Core modification of substituted piperidines as novel inhibitors of HDM2-p53 protein-protein interaction.

The discovery of 3,3-disubstituted piperidine 1 as novel p53-HDM2 inhibitors prompted us to implement subsequent SAR follow up directed towards piperidine core modifications. Conformational restrictions and further functionalization of the piperidine core were investigated as a strategy to gain additional interactions with HDM2. Substitutions at positions 4, 5 and 6 of the piperidine ring were explored.

Substituted piperidines as HDM2 inhibitors.

Novel small molecule HDM2 inhibitor, substituted piperidine, was identified. Initial SAR study indicated potential for several position optimizations. Additional potency enhancement was achieved by introducing a sidechain off the aromatic ring.

Novel benzimidazole inhibitors bind to a unique site in the kinesin spindle protein motor domain.

Affinity selection-mass spectrometry (AS-MS) screening of kinesin spindle protein (KSP) followed by enzyme inhibition studies and temperature-dependent circular dichroism (TdCD) characterization was utilized to identify a series of benzimidazole compounds. This series also binds in the presence of Ispinesib, a known anticancer KSP inhibitor in phase I/II clinical trials for breast cancer. TdCD and AS-MS analyses support simultaneous binding implying existence of a novel non-Ispinesib binding pocket within KSP.

Substituted benzimidazoles: A novel chemotype for small molecule hKSP inhibitors.

Substituted benzimidazoles were profiled as inhibitors of kinesin spindle protein (KSP), an increasingly important target for the development of anticancer drugs. This series demonstrated the monoastral phenotypic response and was found to be active in both enzymatic and cellular-based assays.

Intramolecular inverse-electron-demand Diels-Alder reactions of imidazoles with 1,2,4-triazines: a new route to 1,2,3,4-tetrahydro-1,5-naphthyridines and related heterocycles.

The intramolecular inverse-electron-demand Diels-Alder reaction between imidazoles and 1,2,4-triazines linked by a trimethylene tether from the imidazole N1 position to the triazine C3 proceed in excellent yields to produce 1,2,3,4-tetrahydro-1,5-naphthyridines. The reaction proceeds by a cycloaddition with subsequent loss of nitrogen, followed by a presumed stepwise loss of a nitrile. The analogous intramolecular cycloadditions employing a tetramethylene tether also proceeded to give 2,3,4,5-tetrahydro-1H-pyrido[3,2-b]azepines in acceptable yields.

Dienophilicity of imidazole in inverse electron demand Diels-Alder reactions. 4. Intermolecular reactions with 1,2,4-triazines.

Intermolecular inverse electron demand cycloadditions of 2-substituted imidazoles with various 1,2,4-triazines produced both imidazo[4,5-c]pyridines (3-deazapurines) and pyrido[3,2-d]pyrimid-4-ones (8-deazapteridines). The product distribution was controlled by reactant substituents and influenced by reaction temperature. A regioselective method for the preparation of 6-unsubstituted 1,2,4-triazines was also developed.