Indole Inhibitors of MMP-13 for Arthritic Disorders.

Here, we described the design, by fragment merging and multiparameter optimization, of selective MMP-13 inhibitors that display an appropriate balance of potency and physicochemical properties to qualify as tool compounds suitable for in vivo testing. Optimization of potency was guided by structure-based insights, specifically to replace an ester moiety and introduce polar directional hydrogen bonding interactions in the core of the molecule. By introducing polar enthalpic interactions in this series of inhibitors, the overall beneficial physicochemical properties were maintained. These physicochemical properties translated to excellent drug-like properties beyond potency. In a murine model of rheumatoid arthritis, treatment of mice with selective inhibitors of MMP-13 resulted in a statistically significant reduction in the mean arthritic score vs control when dosed over a 14 day period.

Molecular Complexity and Retrosynthesis.

An atom-environment complexity measure, CA, to assess local changes in complexity during synthetic transformations is described. The complexity measure is based on applying Shannon's equation to the number and diversity of paths up to two bonds in length emanating from an atom node. The method requires no explicit accounting for bond type, stereochemistry, ring membership, symmetry, or molecular size. CA varies with expectation across a number of basic reaction examples and may identify the key disconnections to guide retrosynthesis.

A path based approach to assessing molecular complexity.

An atom environment, path based approach to calculating molecular complexity is described. Based on Shannon's equation, the method transforms the number and diversity of paths emanating from an atom to an atom-complexity from which a number of molecular complexity measures are derived. The method is independent of explicitly predefined features such as ring membership, bond types, chirality or symmetry. These path-based measures of complexity can distinguish subtle differences in molecular structure and an application to the visualization of marketed drugs, including a number of biologics, is presented.

Discovery of a potent and dissociated non-steroidal glucocorticoid receptor agonist containing an alkyl carbinol pharmacophore.

Synthesis and structure-activity relationship (SAR) of a series of alkyl and cycloalkyl containing non-steroidal dissociated glucocorticoid receptor (GR) agonists is reported. This series of compounds was identified as part of an effort to replace the CF3 group in a scaffold represented by 1a. The study culminated in the identification of compound 14, a t-butyl containing derivative, which has shown potent activity for GR, selectivity against the progesterone receptor (PR) and the mineralocorticoid receptor (MR), in vitro anti-inflammatory activity in an IL-6 transrepression assay, and dissociation in a MMTV transactivation counter-screen. In a collagen-induced arthritis mouse model, 14 displayed prednisolone-like efficacy, and lower impact on body fat and free fatty acids than prednisolone at an equivalent anti-inflammatory dose.

Reaction schemes visualized in network form: the syntheses of strychnine as an example.

Representation of synthesis sequences in a network form provides an effective method for the comparison of multiple reaction schemes and an opportunity to emphasize features such as reaction scale that are often relegated to experimental sections. An example of data formatting that allows construction of network maps in Cytoscape is presented, along with maps that illustrate the comparison of multiple reaction sequences, comparison of scaffold changes within sequences, and consolidation to highlight common key intermediates used across sequences. The 17 different synthetic routes reported for strychnine are used as an example basis set. The reaction maps presented required a significant data extraction and curation, and a standardized tabular format for reporting reaction information, if applied in a consistent way, could allow the automated combination of reaction information across different sources.

Substituted pyrazoles as novel sEH antagonist: investigation of key binding interactions within the catalytic domain.

A novel series of pyrazole sEH inhibitors is reported. Lead optimization efforts to replace the aniline core are also described. In particular, 2-pyridine, 3-pyridine and pyridazine analogs are potent sEH inhibitors with favorable CYP3A4 inhibitory and microsomal stability profiles.

Improving potency and selectivity of a new class of non-Zn-chelating MMP-13 inhibitors.

Discovery and optimization of potency and selectivity of a non-Zn-chelating MMP-13 inhibitor with the aid of protein co-crystal structural information is reported. This inhibitor was observed to have a binding mode distinct from previously published MMP-13 inhibitors. Potency and selectivity were improved by extending the hit structure out from the active site into the S1' pocket.

Quinol-4-ones as steroid A-ring mimetics in nonsteroidal dissociated glucocorticoid agonists.

We report on the nuclear receptor binding affinities, cellular activities of transrepression and transactivation, and anti-inflammatory properties of a quinol-4-one and other A-ring mimetic containing nonsteroidal class of glucocorticoid agonists.

A concise asymmetric route for the synthesis of a novel class of glucocorticoid mimetics containing a trifluoromethyl-substituted alcohol.

An asymmetric route was developed for the synthesis of a class of novel glucocorticoid receptor ligand derivatives 1. The key step of this synthesis involves a diastereoselective addition of chiral sulfoxide anion to a trifluoromethyl ketone precursor. The resulting diastereomers are readily separable and can be converted to the corresponding chiral epoxide and chiral alkyne intermediates (2 and 3). This sequence of reactions is suitable for large-scale preparation of these chiral intermediates and derivatives of 1. The absolute stereochemistry of the biologically active enantiomer of these GR ligands has also been determined.

The evolution of synthetic oral drug properties.

An analysis of the properties of 1791 synthetic, oral drugs approved and/or marketed since 1937 demonstrates that the median molecular weight of oral drugs has increased substantially over the past 60 years. Fewer than 5% of approved/marketed oral drugs have more than 4-H bond donors and just 2% have MW>500 and >3 H-bond donors.

A structure-permeability study of small drug-like molecules.

A systematic structure-permeability relationship study on a set of small drug-like molecules with log D values in the range -2.5 to 3 and carrying a diverse array of functionality reveals that the compounds with log D>0 and <3 are highly permeable. Surprisingly, several tetrazole derivatives were found to be substrates for efflux pump(s).

Drugs, leads, and drug-likeness: an analysis of some recently launched drugs.

An analysis of the origins of recently launched drugs reveals that most were derived by modification of known drug structures or from lead structures obtained from the scientific literature. High-throughput screening did not have a significant impact on the derivation of these drugs. The drug structures are very closely related to their leads.