Role of Biotransformation Studies in Minimizing Metabolism-Related Liabilities in Drug Discovery

Metabolism-related liabilities continue to be a major cause of attrition for drug candidates in clinical development. Such problems may arise from the bioactivation of the parent compound to a reactive metabolite capable of modifying biological materials covalently or engaging in redox-cycling reactions leading to the formation of other toxicants. Alternatively, they may result from the formation of a major metabolite with systemic exposure and adverse pharmacological activity. To avert such problems, biotransformation studies are becoming increasingly important in guiding the refinement of a lead series during drug discovery and in characterizing lead candidates prior to clinical evaluation. This article provides an overview of the methods that are used to uncover metabolism-related liabilities in a pre-clinical setting and offers suggestions for reducing such liabilities via the modification of structural features that are used commonly in drug-like molecules

Rare Nuclearities and Unprecedented Structural Motifs in Manganese Cluster Chemistry from the Combined Use of Di-2-Pyridyl Ketone with Selected Diols

The combined use of di-2-pyridyl ketone ((py)2CO) with various diols in Mn cluster chemistry has afforded five new compounds, namely, [Mn11O2(OH)2{(py)2CO2}5(pd)(MeCO2)3(N3)3(NO3)2(DMF)4](NO3)∙2DMF∙H2O (1∙2DMF∙H2O), [Mn11O2(OH)2{(py)2CO2}5(mpd)(MeCO2)3(N3)3(NO3)2(DMF)4](NO3) (2), [Mn12O4(OH)2{(py)2CO2}4(mpd)2(Me3CCO2)4(NO3)4(H2O)6](NO3)2∙2MeCN (3∙2MeCN), [Mn4(OMe)2{(py)2C(OMe)O}2(2-hp)2(NO3)2(DMF)2] (4), and [Mn7{(py)2CO2}4(2-hp)4(NO3)2(DMF)2](ClO4)∙DMF (5∙DMF) ((py)2CO22− and (py)2C(OMe)O− = gem-diol and hemiketal derivatives of di-2-pyridyl ketone, pdH2 = 1,3-propanediol, mpdH2 = 2-metly-1,3-propanediol, 2-hpH2 = 2-(hydroxymethyl)phenol). Complexes 1 and 2 are isostructural, possessing an asymmetric [MnIII5MnII6(μ4-O)(μ3-O)(μ3-OH)(μ-OH)(μ3-OR)2(μ-OR)10(μ-N3)]8+ core. Compound 3 is based on a multilayer [MnIII8MnII4(μ4-O)2(μ3-O)2(μ3-OH)2(μ-OR)12]10+ core, while complex 4 comprises a defective dicubane core. The crystal structure of 5 reveals that it is based on an unusual non-planar [MnIII5MnII2(μ-OR)12]7+ core with a serpentine-like topology. Direct current (dc) magnetic susceptibility studies revealed the presence of dominant antiferromagnetic exchange interactions in complex 3, while ferromagnetic coupling between the Mn ions was detected in the case of compound 5. Fitting of the magnetic data for complex 4 revealed weak antiferromagnetic interactions along the peripheral MnII∙∙∙MnIII ions (Jwb = −0.33 (1) cm−1) and ferromagnetic interactions between the central MnIII∙∙∙MnIII ions (Jbb = 6.28 (1) cm−1)

Heterometallic Mn^III₄Ln₂ (Ln = Dy, Gd, Tb) Cross-Shaped Clusters and Their Homometallic Mn^III₄Mn^II₂ Analogues

The employment of di-2-pyridyl ketone, (py)₂CO, in heterometallic Mn/4f and homometallic Mn cluster chemistry has yielded six Mn^III₄Ln₂ and two Mn^III₄Mn^II₂ structurally related clusters, namely, [Mn₄Ln₂O₂{(py)₂CO₂}₄(NO₃)₂­(RCO₂)₂(H₂O)₆]­(NO₃)₂ (Ln = Gd, <b>1</b>, <b>5</b>; Dy, <b>2</b>; Tb, <b>3</b>; R = Et, <b>1</b>–<b>3</b>; Me, <b>5</b>), [Mn₄Dy₂O₂{(py)₂CO₂}₄(NO₃)₄­(EtCO₂)₂(H₂O)₃(MeOH)]·0.7MeOH·0.8H₂O (<b>4</b>·0.7MeOH·0.8H₂O), [Mn₄Gd₂O₂{(py)₂CO₂}₄(NO₃)₄­(C₆H₄ClCO₂)₂(MeOH)₂(py)₂]·2MeOH (<b>6</b>·2MeOH), [Mn₆O₂{(py)₂CO₂}₄­(py)₄(H₂O)₄]­(ClO₄)₄·4H₂O (<b>7</b>·4H₂O), and [Mn₆O₂{(py)₂CO₂}₄­(NO₃)₄(py)₄] (<b>8</b>), where (py)₂CO₂^2– is the dianion of the <i>gem</i>-diol derivative of (py)₂CO. The compounds possess a new type of cross-shaped structural core, which in the case of <b>1</b>–<b>6</b> is essentially planar, whereas in <b>7</b> and <b>8</b> it deviates from planarity. Clusters <b>1</b>–<b>6</b> are rare examples of Mn/4f species bearing (py)₂CO or its derivatives, despite the fact that this ligand has been well-studied and proven a rich source of more than 200 metal compounds so far. Variable-temperature, solid-state direct-current and alternating-current magnetization studies were performed on complexes <b>1</b>–<b>5</b>, <b>7</b>, and <b>8</b> revealing that the dominant exchange interactions between the metal ions are antiferromagnetic and indicating ground-state spin values of <i>S</i> = 5 (for <b>1</b>), 6 (for <b>5</b>), and 2 (for <b>7</b> and <b>8</b>)

Cross-linguistic patterns in the acquisition of quantifiers

Learners of most languages are faced with the task of acquiring words to talk about number and quantity. Much is known about the order of acquisition of number words as well as the cognitive and perceptual systems and cultural practices that shape it. Substantially less is known about the acquisition of quantifiers. Here, we consider the extent to which systems and practices that support number word acquisition can be applied to quantifier acquisition and conclude that the two domains are largely distinct in this respect. Consequently, we hypothesize that the acquisition of quantifiers is constrained by a set of factors related to each quantifier&apos;s specific meaning. We investigate competence with the expressions for &quot;all,&quot; &quot;none,&quot; &quot;some,&quot; &quot;some not,&quot; and &quot;most&quot; in 31 languages, representing 11 language types, by testing 768 5-y-old children and 536 adults. We found a cross-linguistically similar order of acquisition of quantifiers, explicable in terms of four factors relating to their meaning and use. In addition, exploratory analyses reveal that languageand learner-specific factors, such as negative concord and gender, are significant predictors of variation