Spontaneous Stereoselective Oxidation of Crystalline Avermectin B1a to Its C-8a-(S)-Hydroperoxide.

Prolonged storage of technical abamectin as well as avermectin B1a samples yielded a previously unknown derivative, designated here as compound 1. Detailed NMR analysis and X-ray crystallography allowed us to determine the structure of this compound and revealed the presence of a hydroperoxide group (-OOH) attached stereoselectively with configuration S to the C-8a carbon. This surprising result involves the formation of the peroxide bond in solid crystalline avermectin B1a upon exposure to air with no involvement of light or recognized catalytic factors and is consistent with a topotactic mechanism for the oxidation reaction. Compound 1 is stable in the absence of reducing agents and has potential as a starting point in structural modification of the tetrahydrofuran ring of avermectin B1a. It could also serve as a marker in assessing the quality of stored technical abamectin.

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.

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.

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.

SAR studies of non-zinc-chelating MMP-13 inhibitors: improving selectivity and metabolic stability.

SAR studies to improve the selectivity and metabolic stability of a class of recently discovered MMP-13 inhibitors are reported. Improved selectivity was achieved by modifying interactions with the S1' pocket. Metabolic stability was improved through reduction of inhibitor lipophilicity. This translated into lower in vivo clearance for the preferred compound.

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.

Tetrazole compounds: the effect of structure and pH on Caco-2 cell permeability.

A tetrazole ring is often used in drug discovery as a replacement for the carboxylic acid group. Previous work indicates that compounds containing a tetrazole moiety show asymmetric permeability in Caco-2 cells characteristic of an efflux transporter substrate. The aim of this study is to determine which transporters are responsible for polarization of transport of tetrazole-containing compounds in Caco-2 cells. Results indicate that only select compounds with tetrazole moieties display asymmetric transport. Three compounds (two commercial drug products and one druglike structure) were selected for further studies. Losartan appears to be primarily a P-glycoprotein (P-gp) substrate, as previously reported, but MRP inhibitors such as MK-571 and rifampicin also affect the difference between apical to basolateral and basolateral to apical transport. Pemirolast and phenyltetrazole derivative C are sensitive to P-gp inhibition, but transport seems to be mediated by one or more of the MRP family of transporters. Additionally, lowering the pH from 7.4 to 4.0 eliminates the polarization of permeability in Caco-2 cells. These studies indicate that some tetrazole compounds are susceptible to efflux, therefore caution should be used when choosing an appropriate functional group to replace carboxylic acids when synthesizing a drug candidate.

The Pistoia Alliance Controlled Substance Compliance Service Project: from start to finish.

Pharmaceutical companies and other life science R&D organizations routinely work with controlled substances, and must have adequate controls in place to meet the legislative requirements of the countries in which they operate. Controlled substances include a range of narcotics and psychotropic drugs, which are covered by increasingly complex legislation as legislators attempt to keep up with a rapidly changing environment. This legislation must be interpreted and transformed from legal wording into chemical structures to be used effectively. Over the past year a working party of pharmaceutical and technology companies has come together under the umbrella of the Pistoia Alliance to define a Controlled Substance Compliance Service. We describe the benefits of bringing together this group of experts to solve the pre-competitive issue of controlled substance management.

Discovery of potent, selective chymase inhibitors via fragment linking strategies.

Chymase plays an important and diverse role in the homeostasis of a number of cardiovascular processes. Herein, we describe the identification of potent, selective chymase inhibitors, developed using fragment-based, structure-guided linking and optimization techniques. High-concentration biophysical screening methods followed by high-throughput crystallography identified an oxindole fragment bound to the S1 pocket of the protein exhibiting a novel interaction pattern hitherto not observed in chymase inhibitors. X-ray crystallographic structures were used to guide the elaboration/linking of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over cathepsin G and that mitigated a number of liabilities associated with poor physicochemical properties of the series it was derived from.

Fragment-based discovery of indole inhibitors of matrix metalloproteinase-13.

Matrix metalloproteases (MMPs) play an important role in cartilage homeostasis under both normal and inflamed disease states and, thus, have become attractive targets for the treatment of arthritic diseases. Herein, we describe the identification of a potent, selective MMP-13 inhibitor, developed using fragment-based structure-guided lead identification and optimization techniques. Virtual screening methods identified a novel, indole-based MMP-13 inhibitor that bound into the S1' pocket of the protein exhibiting a novel interaction pattern hitherto not observed in MMP-13 inhibitors. X-ray crystallographic structures were used to guide the elaboration of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over nine other MMP isoforms tested.

Discovery and SAR study of novel dihydroquinoline-containing glucocorticoid receptor agonists.

We have recently reported the discovery of a novel class of glucocorticoid receptor (GR) antagonists, exemplified by 3, containing a 1,2-dihydroquinoline molecular scaffold. Further SAR studies of these antagonists uncovered chemical modifications conveying agonist functional activity to this series. These agonists exhibit good GR binding affinity and are selective against other nuclear hormone receptors.

Identification of dissociated non-steroidal glucocorticoid receptor agonists.

A new series of ligands for the glucocorticoid receptor (GR) is described. SAR development was guided by docking 3 into the GR active site and optimizing an unsubstituted phenyl ring for key interactions found in the steroid A-ring binding pocket. To identify compounds with an improved side effect profile over marketed steroids the functional activity of compounds was evaluated in cell based assays for transactivation (aromatase) and transrepression (IL-6). Through this effort, 36 has been identified as a partial agonist with a dissociated profile in these cell based assays.

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.

Discovery and SAR study of novel dihydroquinoline containing glucocorticoid receptor ligands.

We report the discovery of a novel class of glucocorticoid receptor (GR) ligands based on 1,2-dihydroquinoline molecular scaffold. The compounds exhibit good GR binding affinity and selectivity profile against other nuclear hormone receptors.

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.