Novel 6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene analogues as potent and selective 5-HT2C agonists for the treatment of metabolic disorders

Tye, Heather; Mueller, Stephan G.; Prestle, J.; Scheuerer, Stefan; Schindler, Marcus; Nosse, Bernd; Prévost, Natacha; Brown, Christopher J.; Heifetz, Alexander; Moeller, Clemens; Pedret-Dunn, Anna; Whittaker, Mark

doi:10.1016/j.bmcl.2010.11.089

Cited by 23 publications

(23 citation statements)

References 12 publications

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“…Since its first application to measuring the hERG channel for safety screening (Kiss et al, 2003), this technique has been well validated for a number of robots. It is now widely applied to reduce the liability of compound series’ towards the hERG channel as part of safety pharmacology assessment early during medicinal chemistry compound development (Kutchinsky et al, 2003; Davenport et al, 2010; Riether et al, 2011; Tye et al, 2011). Reported correlations of biophysical channel properties (Figure 2) as well as pharmacological compound properties between automated (planar, chip-based) and manual (pipette-based) patch-clamp investigations are generally excellent (Kutchinsky et al, 2003; Xu et al, 2003; Tao et al, 2004; Bridgland-Taylor et al, 2006; Jones et al, 2009; Davenport et al, 2010; Golden et al, 2011).…”

Section: Automated Patch-clamp Electrophysiology Alleviates a Bottlenmentioning

confidence: 99%

“…Never before has it been practically possible for pharmaceutical companies to screen compounds on the order of tens of thousands against an ion channel target by use of a direct functional readout, and thus avoiding the potential false positives and/or negatives associated to other, more indirect (such as fluorescence assay or binding techniques), high-throughput screening methods. This has allowed drug developers to move cardiac ion channel safety screening earlier into the drug development pipeline, and to mitigate potential cardiac safety liabilities of potent compound series (Davenport et al, 2010; Riether et al, 2011; Tye et al, 2011). …”

Section: Automated Patch-clamp Electrophysiology Alleviates a Bottlenmentioning

confidence: 99%

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Automated electrophysiology makes the pace for cardiac ion channel safety screening

Möller

Witchel

2011

Front. Pharmacol.

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The field of automated patch-clamp electrophysiology has emerged from the tension between the pharmaceutical industry’s need for high-throughput compound screening versus its need to be conservative due to regulatory requirements. On the one hand, hERG channel screening was increasingly requested for new chemical entities, as the correlation between blockade of the ion channel coded by hERG and torsades de pointes cardiac arrhythmia gained increasing attention. On the other hand, manual patch-clamping, typically quoted as the “gold-standard” for understanding ion channel function and modulation, was far too slow (and, consequently, too expensive) for keeping pace with the numbers of compounds submitted for hERG channel investigations from pharmaceutical R&D departments. In consequence it became more common for some pharmaceutical companies to outsource safety pharmacological investigations, with a focus on hERG channel interactions. This outsourcing has allowed those pharmaceutical companies to build up operational flexibility and greater independence from internal resources, and allowed them to obtain access to the latest technological developments that emerged in automated patch-clamp electrophysiology – much of which arose in specialized biotech companies. Assays for nearly all major cardiac ion channels are now available by automated patch-clamping using heterologous expression systems, and recently, automated action potential recordings from stem-cell derived cardiomyocytes have been demonstrated. Today, most of the large pharmaceutical companies have acquired automated electrophysiology robots and have established various automated cardiac ion channel safety screening assays on these, in addition to outsourcing parts of their needs for safety screening.

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Section: Automated Patch-clamp Electrophysiology Alleviates a Bottlenmentioning

confidence: 99%

Section: Automated Patch-clamp Electrophysiology Alleviates a Bottlenmentioning

confidence: 99%

Automated electrophysiology makes the pace for cardiac ion channel safety screening

Möller

Witchel

2011

Front. Pharmacol.

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“…The hierarchical GPCR modelling protocol (HGMP) has been developed to support GPCR SBDD programmes. HGMP has been successfully applied in GPCR drug discovery projects such as MCH-1R for obesity treatment [30], the orexin-1 and -2 receptors (OX 1 R and OX 2 R) for insomnia [31,32], the 5-HT 2C for the treatment of metabolic disorders [33,34] and in other confidential drug discovery programmes. Additionally, the HGMP technology was used in the solving of the two H 1 R crystals structures [4] bound to the second and third generation antihistamines: cetirizine and fexofenadine.…”

Section: Introductionmentioning

confidence: 99%

Using the fragment molecular orbital method to investigate agonist–orexin-2 receptor interactions

Heifetz

Aldeghi

Chudyk

et al. 2016

Biochemical Society Transactions

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The understanding of binding interactions between any protein and a small molecule plays a key role in the rationalization of affinity and selectivity and is essential for an efficient structure-based drug discovery (SBDD) process. Clearly, to begin SBDD, a structure is needed, and although there has been fantastic progress in solving G-protein-coupled receptor (GPCR) crystal structures, the process remains quite slow and is not currently feasible for every GPCR or GPCR–ligand complex. This situation significantly limits the ability of X-ray crystallography to impact the drug discovery process for GPCR targets in ‘real-time’ and hence there is still a need for other practical and cost-efficient alternatives. We present here an approach that integrates our previously described hierarchical GPCR modelling protocol (HGMP) and the fragment molecular orbital (FMO) quantum mechanics (QM) method to explore the interactions and selectivity of the human orexin-2 receptor (OX2R) and its recently discovered nonpeptidic agonists. HGMP generates a 3D model of GPCR structures and its complexes with small molecules by applying a set of computational methods. FMO allows ab initio approaches to be applied to systems that conventional QM methods would find challenging. The key advantage of FMO is that it can reveal information on the individual contribution and chemical nature of each residue and water molecule to the ligand binding that normally would be difficult to detect without QM. We illustrate how the combination of both techniques provides a practical and efficient approach that can be used to analyse the existing structure–function relationships (SAR) and to drive forward SBDD in a real-world example for which there is no crystal structure of the complex available.

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“…Pyrazolo [1,5-a]pyrimidines are of chemical and pharmacological importance as purine analogues, and derivatives have been applied in various therapeutic areas such as antitumor, [15][16][17][18][19] antidepressant, [20][21] antibacterial, 22 antiviral, 23 antidiabetic 24 and antihypertensive agents. 25,26 Representatives of the SFK29 series (1-6, Figure 1) were selected for resynthesis based on their activities (MIC 99 < 5 µM) and confirmatory testing Based on its structural novelty, broad activity, and acceptable potencies, the aminopyrazolo[1,5-a]pyrimidine series was selected for a medicinal chemistry optimisation campaign.…”

Section: Introductionmentioning

confidence: 99%

Aminopyrazolo[1,5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: Structure activity relationships and ADME characterization

Melo

Feng

Westhuyzen

et al. 2015

Bioorganic & Medicinal Chemistry

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Whole-cell high-throughput screening of a diverse SoftFocus library against Mycobacterium tuberculosis (Mtb) generated a novel aminopyrazolo[1,5-a]pyrimidine hit series. The synthesis and structure activity relationship studies identified compounds with potent antimycobacterial activity. The SAR of over 140 compounds shows that the 2-pyridylmethylamine moiety at the C-7 position of the pyrazolopyrimidine scaffold was important for Mtb activity, whereas the C-3 position offered a higher degree of flexibility. The series was also profiled for in vitro cytotoxicity and microsomal metabolic stability as well as physicochemical properties. Consequently liabilities to be addressed in a future lead optimization campaign have been identified.

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Novel 6,7,8,9-tetrahydro-5H-1,4,7,10a-tetraaza-cyclohepta[f]indene analogues as potent and selective 5-HT2C agonists for the treatment of metabolic disorders

Cited by 23 publications

References 12 publications

Automated electrophysiology makes the pace for cardiac ion channel safety screening

Automated electrophysiology makes the pace for cardiac ion channel safety screening

Using the fragment molecular orbital method to investigate agonist–orexin-2 receptor interactions

Aminopyrazolo[1,5-a]pyrimidines as potential inhibitors of Mycobacterium tuberculosis: Structure activity relationships and ADME characterization

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