Blockade of hERG K؉ channels in the heart is an unintentional side effect of many drugs and can induce cardiac arrhythmia and sudden death. It has become common practice in the past few years to screen compounds for hERG channel activity early during the drug discovery process. Understanding the molecular basis of drug binding to hERG is crucial for the rational design of medications devoid of this activity. We previously identified 2 aromatic residues, Tyr-652 and Phe-656, located in the S6 domain of hERG, as critical sites of interaction with structurally diverse drugs. Here, Tyr-652 and Phe-656 were systematically mutated to different residues to determine how the physicochemical properties of the amino acid side group affected channel block by cisapride, terfenadine, and MK-499. The potency for block by all three drugs was well correlated with measures of hydrophobicity, especially the twodimensional approximation of the van der Waals hydrophobic surface area of the side chain of residue 656. For residue 652, an aromatic side group was essential for high affinity block, suggesting the importance of a cation-interaction between Tyr-652 and the basic tertiary nitrogen of these drugs. hERG also lacks a Pro-Val-Pro motif common to the S6 domain of most other voltagegated K ؉ channels. Introduction of Pro-Val-Pro into hERG reduced sensitivity to drugs but also altered channel gating. Together, these findings assign specific residues to receptor fields predicted by pharmacophore models of hERG channel blockers and provide a refined molecular understanding of the drug binding site. Long QT syndrome (LQTS)1 is a disorder of ventricular repolarization that predisposes affected individuals to cardiac arrhythmia and sudden death. Inherited LQTS is caused by mutations in K ϩ or Na ϩ ion channel genes or ankyrin-B (1, 2). Acquired LQTS is more common and can be induced as an unintended and rare side effect of treatment with many structurally diverse medications. In the past few years, several commonly used drugs (e.g. terfenadine, cisapride, sertindole, thioridazine, grepafloxacin) were withdrawn from the market, or their approved use was severely restricted, when it was discovered that they caused arrhythmia or were associated with unexplained sudden death, albeit very infrequently (3). The molecular basis of drug-induced LQTS is block of human ether-a-go-go related gene (hERG) channels that conduct I Kr , the rapid delayed rectifier K ϩ current important for repolarization of cardiac action potentials (4, 5). A reduction in I Kr prolongs the action potential duration of ventricular myocytes, lengthens the QT interval and increases dispersion as measured by ECG recordings, and increases the risk of torsades de pointes, a ventricular tachyarrhythmia that can degenerate into fibrillation and cause sudden death. In a laboratory setting, it is possible to induce arrhythmia in animals with drugs that block voltage-gated K ϩ (Kv) channels other than hERG. However, in clinical practice, drug-induced LQTS is always attributable...

Replacement of the central, para-substituted fluorophenyl ring in the γ-secretase inhibitor 1 (BMS-708,163) with the bicyclo[1.1.1]pentane motif led to the discovery of compound 3, an equipotent enzyme inhibitor with significant improvements in passive permeability and aqueous solubility. The modified biopharmaceutical properties of 3 translated into excellent oral absorption characteristics (~4-fold ↑ C(max) and AUC values relative to 1) in a mouse model of γ-secretase inhibition. In addition, SAR studies into other fluorophenyl replacements indicate the intrinsic advantages of the bicyclo[1.1.1]pentane moiety over conventional phenyl ring replacements with respect to achieving an optimal balance of properties (e.g., γ-secretase inhibition, aqueous solubility/permeability, in vitro metabolic stability). Overall, this work enhances the scope of the [1.1.1]-bicycle beyond that of a mere "spacer" unit and presents a compelling case for its broader application as a phenyl group replacement in scenarios where the aromatic ring count impacts physicochemical parameters and overall drug-likeness.

It is hypothesized that selective muscarinic M1 subtype activation could be a strategy to provide cognitive benefits to schizophrenia and Alzheimer's disease patients while minimizing the cholinergic side effects observed with nonselective muscarinic orthosteric agonists. Selective activation of M1 with a positive allosteric modulator (PAM) has emerged as a new approach to achieve selective M1 activation. This manuscript describes the development of a series of M1-selective pyridone and pyridine amides and their key pharmacophores. Compound 38 (PF-06767832) is a high quality M1 selective PAM that has well-aligned physicochemical properties, good brain penetration and pharmacokinetic properties. Extensive safety profiling suggested that despite being devoid of mAChR M2/M3 subtype activity, compound 38 still carries gastrointestinal and cardiovascular side effects. These data provide strong evidence that M1 activation contributes to the cholinergic liabilities that were previously attributed to activation of the M2 and M3 receptors.

We have observed previously that modification of ring size and substitution pattern may be used as a strategy to mitigate the metabolic instability of cycloalkyl ethers. In this article, we introduce a medicinal chemistry design parameter named "lipophilic metabolism efficiency" (LipMetE) that indicates that these changes in metabolic stability can be largely ascribed to changes in lipophilicity. Our matched molecular pair analysis also indicates that this finding is a general phenomenon, widely observed across different chemotypes. It is our hope that both the LipMetE design parameter and the results from our pairwise analysis will be useful tools for medicinal chemists.

Experimental IC(50) data for 314 selective cyclooxygenase-2 (COX-2) inhibitors are used to develop quantitation and classification models as a potential screening mechanism for larger libraries of target compounds. Experimental log(IC(50)) values ranged from 0.23 to > or = 5.00. Numerical descriptors encoding solely topological information are calculated for all structures and are used as inputs for linear regression, computational neural network, and classification analysis routines. Evolutionary optimization algorithms are then used to search the descriptor space for information-rich subsets which minimize the rms error of a diverse training set of compounds. An eight-descriptor model was identified as a robust predictor of experimental log(IC(50)) values, producing a root-mean-square error of 0.625 log units for an external prediction set of inhibitors which took no part in model development. A k-nearest neighbor classification study of the data set discriminating between active and inactive members produced a nine-descriptor model able to accurately classify 83.3% of the prediction set compounds correctly.

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The microsolvated state of a molecule, represented by its interactions with only a small number of solvent molecules, can play a key role in determining the observable bulk properties of the molecule. This is especially true in cases where strong local hydrogen bonding exists between the molecule and the solvent. One method that can probe the microsolvated states of charged molecules is differential mobility spectrometry (DMS), which rapidly interrogates an ion’s transitions between a solvated and desolvated state in the gas phase (i.e., few solvent molecules present). However, can the results of DMS analyses of a class of molecules reveal information about the bulk physicochemical properties of those species? Our findings presented here show that DMS behaviors correlate strongly with the measured solution phase pKa and pKb values, and cell permeabilities of a set of structurally related drug molecules, even yielding high-resolution discrimination between isomeric forms of these drugs. This is due to DMS’s ability to separate species based upon only subtle (yet predictable) changes in structure: the same subtle changes that can influence isomers’ different bulk properties. Using 2-methylquinolin-8-ol as the core structure, we demonstrate how DMS shows promise for rapidly and sensitively probing the physicochemical properties of molecules, with particular attention paid to drug candidates at the early stage of drug development. This study serves as a foundation upon which future drug molecules of different structural classes could be examined.

Strategic replacement of one or more hydrogen atoms with fluorine atom(s) is a common tactic to improve potency at a given target and/or to modulate parameters such as metabolic stability and pKa. Molecular weight (MW) is a key parameter in design, and incorporation of fluorine is associated with a disproportionate increase in MW considering the van der Waals radius of fluorine versus hydrogen. Herein we examine a large compound data set to understand the effect of introducing fluorine on the risk of encountering P-glycoprotein mediated efflux (as measured by MDR efflux ratio), passive permeability, lipophilicity, and metabolic stability. Statistical modeling of the MDR ER data demonstrated that an increase in MW as a result of introducing fluorine atoms does not lead to higher risk of P-gp mediated efflux. Fluorine-corrected molecular weight (MWFC), where the molecular weight of fluorine has been subtracted, was found to be a more relevant descriptor.