Torsion Library Reloaded: A New Version of Expert-Derived SMARTS Rules for Assessing Conformations of Small Molecules

The Torsion Library contains hundreds of rules for small molecule conformations which have been derived from the Cambridge Structural Database (CSD) and are curated by molecular design experts. The torsion rules are encoded as SMARTS patterns and categorize rotatable bonds via a traffic light coloring scheme. We have systematically revised all torsion rules to better identify highly strained conformations and minimize the number of false alerts for CSD small molecule X-ray structures. For this new release, we added or substantially modified 78 torsion patterns and reviewed all angles and tolerance intervals. The overall number of red alerts for a filtered CSD data set with 130 000 structures was reduced by a factor of 4 compared to the predecessor. This is of clear advantage in 3D virtual screening where hits should only be removed by a conformational filter if they are in energetically inaccessible conformations

Torsion Angle Preferences in Druglike Chemical Space: A Comprehensive Guide

Crystal structure databases offer ample opportunities to derive small molecule conformation preferences, but the derived knowledge is not systematically applied in drug discovery research. We address this gap by a comprehensive and extendable expert system enabling quick assessment of the probability of a given conformation to occur. It is based on a hierarchical system of torsion patterns that cover a large part of druglike chemical space. Each torsion pattern has associated frequency histograms generated from CSD and PDB data and, derived from the histograms, traffic-light rules for frequently observed, rare, and highly unlikely torsion ranges. Structures imported into the corresponding software are annotated according to these rules. We present the concept behind the tree of torsion patterns, the design of an intuitive user interface for the management and usage of the torsion library, and we illustrate how the system helps analyze and understand conformation properties of substructures widely used in medicinal chemistry

Torsion Angle Preferences in Druglike Chemical Space: A Comprehensive Guide

Crystal structure databases offer ample opportunities to derive small molecule conformation preferences, but the derived knowledge is not systematically applied in drug discovery research. We address this gap by a comprehensive and extendable expert system enabling quick assessment of the probability of a given conformation to occur. It is based on a hierarchical system of torsion patterns that cover a large part of druglike chemical space. Each torsion pattern has associated frequency histograms generated from CSD and PDB data and, derived from the histograms, traffic-light rules for frequently observed, rare, and highly unlikely torsion ranges. Structures imported into the corresponding software are annotated according to these rules. We present the concept behind the tree of torsion patterns, the design of an intuitive user interface for the management and usage of the torsion library, and we illustrate how the system helps analyze and understand conformation properties of substructures widely used in medicinal chemistry

6‑Alkoxy-5-aryl-3-pyridinecarboxamides, a New Series of Bioavailable Cannabinoid Receptor Type 1 (CB1) Antagonists Including Peripherally Selective Compounds

We identified 6-alkoxy-5-aryl-3-pyridinecarboxamides as potent CB1 receptor antagonists with high selectivity over CB2 receptors. The series was optimized to reduce lipophilicity compared to rimonabant to achieve peripherally active molecules with minimal central effects. Several compounds that showed high plasma exposures in rats were evaluated in vivo to probe the contribution of central vs peripheral CB1 agonism to metabolic improvement. Both rimonabant and <b>14g</b>, a potent brain penetrant CB1 receptor antagonist, significantly reduced the rate of body weight gain. However, <b>14h</b>, a molecule with markedly reduced brain exposure, had no significant effect on body weight. PK studies confirmed similarly high exposure of both <b>14h</b> and <b>14g</b> in the periphery but 10-fold lower exposure in the brain for <b>14h</b>. On the basis of these data, which are consistent with reported effects in tissue-specific CB1 receptor KO mice, we conclude that the metabolic benefits of CB1 receptor antagonists are primarily centrally mediated as originally believed

β‑Secretase (BACE1) Inhibitors with High in Vivo Efficacy Suitable for Clinical Evaluation in Alzheimer’s Disease

An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the p<i>K</i>_a and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF₃ substituted oxazine <b>89</b>, a potent and highly brain penetrant BACE1 inhibitor, was able to reduce significantly CSF Aβ40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of Aβ40 and 42 even after 24 h. In contrast to <b>89</b>, compound <b>1b</b> lacking the CF₃ group was virtually inactive in vivo