A series of isoquinuclidine benzamides as glycine uptake inhibitors for the treatment of schizophrenia are described. Potency, lipophilicity, and intrinsic human microsomal clearance were parameters for optimization. Potency correlated with the nature of the ortho substituents of the benzamide ring, and reductions in lipophilicity could be achieved through heteroatom incorporation in the benzamide and pendant phenyl moieties. Improvements in human CLint were achieved through changes in ring size and the N-alkyl group of the isoquinuclidine itself, with des-alkyl derivatives (40-41, 44) demonstrating the most robust microsomal stability. Dimethylbenzamide 9 was tested in a mouse MK801 LMA assay and had a statistically significant attenuation of locomotor activity at 3 and 10 mu mol/kg compared to control. (C) 2018 Elsevier Ltd. All rights reserved.

Positron emission tomography (PET), together with a suitable radioligand, is one of the more prominent methods for measuring changes in synaptic neurotransmitter concentrations in vivo. The radioligand of choice for such measurements on the cholinergic system is the muscarinic receptor antagonist N-[1-11C]propyl-3-piperidyl benzilate (PPB). In an effort to overcome the shortcomings with the technically cumbersome synthesis of [11C]PPB, we designed and synthesized four structurally related analogues of PPB, of which (S,R)-1-methylpiperidin-3-yl)2-cyclopentyl-2-hydroxy-2-phenylacetate (1) was found to bind muscarinic receptors with similar affinity as PPB (3.5 vs 7.9 nM, respectively). (S,R)-1 was radiolabeled via N-11C-methylation at high radiochemical purity (>99%) and high specific radioactivity (>130 GBq/μmol). In vitro studies by autoradiography on human brain tissue and in vivo studies by PET in nonhuman primates demonstrated excellent signal-to-noise ratios and a kinetic profile in brain comparable to that of [11C]PBB. (S,R)-[11C]1 is a promising candidate for measuring changes in endogenous acetylcholine concentrations.

A practical and asymmetric synthesis of a small-molecule CXCR7 modulator featuring a highly functionalized and hindered tertiary β-amino amide framework is reported. The cornerstone of this strategy relied on the intermediacy of a reactive aziridinium species, which, following regioselective ring opening with cyanide, furnished the desired chiral β-tertiary amino nitrile for further elaboration. As a means of further highlighting this synthetic strategy, an expanded scope of hindered β-amino amide synthesis is also presented.

New strategies to potentially improve drug safety and efficacy emerge with allosteric programs. Biased allosteric modulators can be designed with high subtype selectivity and defined receptor signaling endpoints, however, selecting the most meaningful parameters for optimization can be perplexing. Historically, “potency hunting” at the expense of physicochemical and pharmacokinetic optimization has led to numerous tool compounds with excellent pharmacological properties but no path to drug development. Conversely, extensive physicochemical and pharmacokinetic screening with only post hoc bias and allosteric characterization has led to inefficacious compounds or compounds with on-target toxicities. This field is rapidly evolving with new mechanistic understanding, changes in terminology, and novel opportunities. The intent of this digest is to summarize current understanding and debates within the field. We aim to discuss, from a medicinal chemistry perspective, the parameter choices available to drive SAR.

Fragment-based drug design (FBDD) relies on direct elaboration of fragment hits and typically requires high resolution structural information to guide optimization. In fragment-assisted drug discovery (FADD), fragments provide information to guide selection and design but do not serve as starting points for elaboration. We describe FADD and high-throughput screening (HTS) campaign strategies conducted in parallel against PDE10A where fragment hit co-crystallography was not available. The fragment screen led to prioritized fragment hits (IC50’s ∼500μM), which were used to generate a hypothetical core scaffold. Application of this scaffold as a filter to HTS output afforded a 4μM hit, which, after preparation of a small number of analogs, was elaborated into a 16nM lead. This approach highlights the strength of FADD, as fragment methods were applied despite the absence of co-crystallographical information to efficiently identify a lead compound for further optimization.

We describe the discovery and advancement of a novel series of TRPA1 antagonist having an aryl-N-(3-(alkylamino)-5-(trifluoromethyl)phenyl)benzamide scaffold. The physical and in vitro DMPK profiles are discussed.

A series of TRPA1 antagonists is described having a 4-aryloxy-1H-pyrrolo[3,2-c]pyridine or a 1-aryloxyisoquinoline scaffold. These compounds have high ligand efficiency and favorable physical properties and may thus serve as scaffolds for further optimization.

The Transient Receptor Potential A1 (TRPA1) ion channel has evolved in animals to respond to signals from a variety of sensory stimuli. Many structural determinants of its multimodal activation have been identified to date. TRPA1 activities include responses to exogenous chemical irritants, responses to endogenous inflammatory mediators, zinc, voltage, temperature or stretch and subtle yet critical modulation by calcium ions. TRPA1 has emerged as an important target for several types of pain and inflammatory conditions because of its limited expression profile and its demonstrated roles in mediating different types of pain and sensitization of peripheral sensory afferents. Despite observed species differences in channel pharmacology, recent genetic evidence in human brings some hope that preclinical efficacy in disease models will translate to patient condition. During the past decade, various groups have investigated the development of a new class of analgesic drugs or anti-tussive agents aimed at blocking TRPA1 activity in primary sensory afferents. Several companies are advancing toward clinical proof of concept studies. This review aims to summarize key advances in the understanding of TRPA1 with regard to its roles and implications for patient conditions.

During inflammation, several Transient Receptor Potential (TRP) channels are directly or indirectly activated by inflammatory signaling molecules and microenvironmental changes including heat, oxidative conditions or low pH. In either case, specific TRP isoforms participate in chains of pro- or anti-inflammatory signaling cascades often including activation of transcription factors, protein kinases and phospholipases, which result in signal integration or amplification. In a few cases, their potentials as therapeutic targets for inflammatory conditions like pruritis, cystitis, dermatitis, asthma among other conditions are investigated pre-clinically or clinically by pioneering academic groups and industries. Significant efforts are still devoted to the understanding of the detailed physiological roles played by TRP channels during inflammation. This review intends to summarize key biological findings and reports of drug discovery activities when available, in an overview of the current status and recent developments in the field.

We describe the development of a novel fragment screening methodology employing a plate-based optical biosensor system that can operate in a 384-well format. The method is based on the "inhibition in solution assay" (ISA) approach using an immobilized target definition compound (TDC) that has been specifically designed for this purpose by making use of available structural information. We demonstrate that this method is robust and is sufficiently sensitive to detect fragment hits as weak as KD 500 μM when confirmed in a conventional surface plasmon resonance approach. The application of the plate-based screen, the identification of fragment inhibitors of PDE10A, and their structural characterization are all discussed in a forthcoming paper.

Preface vii Contributors xi Introduction 1 Alan J. Cross 1 Dopaminergic Hypothesis of Schizophrenia: A Historical Perspective 5 Aurelija Jucaite and Svante Nyberg 2 Dopamine D2/D3 Partial Agonists as Antipsychotics 37 Philip G. Strange 3 D1/D5 Dopamine Agonists as Pharmacotherapy for Schizophrenia 51 Kevin N. Boyd and Richard B. Mailman 4 Phosphodiesterase Inhibitors as a Novel Therapeutic Approach for Schizophrenia 85 Judith A. Siuciak and William J. Pitts 5 Glutamatergic Synaptic Dysregulation in Schizophrenia 115 Joseph T. Coyle, Alo Basu, and Michael Benneyworth 6 Metabotropic Glutamate 2/3 Receptor Agonists and Positive Allosteric Modulators of Metabotropic Glutamate Receptor 2 as Novel Agents for the Treatment of Schizophrenia 143 Gerard J. Marek, Bruce J. Kinon, David L. McKinzie, Jeffrey M. Schkeryantz, and James A. Monn 7 AMPA Receptor Positive Modulators 187 John A. Morrow, John K.F. Maclean, and Craig Jamieson 8 Progress in the Exploration and Development of GlyT1 Inhibitors for Schizophrenia 233 Jeffrey S. Albert and Michael W. Wood 9 Combined Dopamine D2 and 5-Hydroxytryptamine (5-HT)1A Receptor Strategies for the Treatment of Schizophrenia: A Pharmacological and Chemical Perspective 255 Andrew C. McCreary, Roelof W. Feenstra, and Caitlin A. Jones 10 5-HT2C and 5-HT6 Receptor Targeted Emerging Approaches in Schizophrenia 273 Sharon Rosenzweig-Lipson, John Dunlop, Lee E. Schechter, Thomas A. Comery, Jonathan Gross, and Karen L. Marquis 11 The Cholinergic Hypothesis: An Introduction to the Hypothesis and a Short History 295 Joseph I. Friedman, Isabella Kanellopoulou, and Vladan Novakovic 12 7 Nicotinic Acetylcholine Receptors in the Treatment of Schizophrenia 319 Mihaly Hajos and Bruce N. Rogers 13 Muscarinic Acetylcholine Receptors as Novel Targets for the Development of Therapeutics for Schizophrenia 355 Christian C. Felder, David L. McKinzie, Richard C. Thompson, and Bin Liu 14 Will Modulation of Neuropeptide Receptors Produce the Next Generation of Antipsychotic Drugs? A Focus on the Neurokinin and Neurotensin Systems 381 Lee A. Dawson, Paul W. Smith, and Jeannette M. Watson 15 GABA and Schizophrenia 425 John H. Kehne and George D. Maynard Index 469

Chapter 8 Progress in the Exploration and Development of GlyT1 Inhibitors for Schizophrenia Jeffrey S. Albert, Jeffrey S. Albert Department of Chemistry, CNS & Pain Innovative Medicines, AstraZeneca, Wilmington, DE, USASearch for more papers by this authorMichael W. Wood, Michael W. Wood CNS & Pain Innovative Medicines Unit, AstraZeneca, Wilmington, DE, USASearch for more papers by this author Jeffrey S. Albert, Jeffrey S. Albert Department of Chemistry, CNS & Pain Innovative Medicines, AstraZeneca, Wilmington, DE, USASearch for more papers by this authorMichael W. Wood, Michael W. Wood CNS & Pain Innovative Medicines Unit, AstraZeneca, Wilmington, DE, USASearch for more papers by this author Book Editor(s):Jeffrey S. Albert, Jeffrey S. Albert Department of Chemistry, CNS & Pain Innovative Medicines, AstraZeneca, Wilmington, DE, USASearch for more papers by this authorMichael W. Wood, Michael W. Wood CNS & Pain Innovative Medicines Unit, AstraZeneca, Wilmington, DE, USASearch for more papers by this author First published: 24 June 2012 https://doi.org/10.1002/9781118309421.ch8Citations: 1 AboutPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShareShare a linkShare onEmailFacebookTwitterLinkedInRedditWechat Summary This chapter contains sections titled: Background The NMDAR Hypofunction Model Expression and Genetics Support for GlyT1 as a Therapeutic Target for Schizophrenia Safety Considerations Mechanistic Differences Among GlyT1 Inhibitors Clinical Development Summary References REFERENCES van Os, J., Kapur, S. (2009). Schizophrenia. Lancet, 374, 635–645. 10.1016/S0140-6736(09)60995-8 CASPubMedWeb of Science®Google Scholar Lindsley, C. (2010). Up from the ashes. The importance of not condemning a mechanism based on a single chemotype. 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Using a modification of the route described by Clardy and Hughes et al., 2,4-methanoproline hydrochloride (1) was prepared in four steps and 70% overall yield from dl-serine methyl ester.

An efficient synthetic route based on generation and subsequent electrophilic reaction of a Boc-protected azabicyclo[2.2.1]heptane anion to prepare a potent GlyT1 uptake inhibitor (1) is described. (C) 2010 Elsevier Ltd. All rights reserved.

The neurokinin-3 (NK3) receptor is regarded as a potential novel target for treating patients with schizophrenia. Herein we report the synthesis and SAR of a series of C3-alkylsulfoxide substituted quinolines as potent NK3 receptor antagonists. These compounds have excellent NK3 functional activity, good selectivity and drug-like properties. Several key compounds have good in vitro/in vivo DMPK characteristics, and are active in a gerbil locomotor activity model.

A novel series of glycine transporter 1 (GlyT1) inhibitors is described. Scoping of the heterocycle moiety of hit 4-chlorobenzenesulfonamide 1 led to replacement of the piperidine with an azepane for a modest increase in potency. Phenyl sulfonamides proved superior to alkyl and non-phenyl aromatic sulfonamides, while subsequent ortho substitution of the 2-(azepan-1-yl)-2-phenylethanamine aromatic ring yielded 39 (IC(50) 37 nM, solubility 14 mu M), the most potent GlyT1 inhibitor in this series. Favorable brain-plasma ratios were observed for select compounds in pharmacokinetic studies to evaluate CNS penetration. (c) 2010 Elsevier Ltd. All rights reserved.