Designed multiple ligands in metabolic disease research: from concept to platform

Gattrell, William; Johnstone, Craig; Patel, Shuchi; Smith, Christine; Scheel, Andreas A.; Schindler, Marcus

doi:10.1016/j.drudis.2013.02.006

Cited by 19 publications

(14 citation statements)

References 16 publications

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“…It was merged with donepenzil in order to obtain multi-target-directed ligands (MTDL) capable of inhibiting both cholinesterases and oxidative stress simultaneously [ 132 ]. The synthesis of MTDL, also known as designed multiple ligands [ 133 ], is a new avenue in medicinal chemistry used not only in AD but also in several other research fields [ 134 , 135 , 136 ]. Recently, the benzisoselenazolone scaffold was merged with clioquinol, a compound known for its ability to chelate metals and inhibit Aβ deposits.…”

Section: Anti-neurodegenerative Disordersmentioning

confidence: 99%

Ebselen and Analogues: Pharmacological Properties and Synthetic Strategies for Their Preparation

2021

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Ebselen is the leader of selenorganic compounds, and starting from its identification as mimetic of the key antioxidant enzyme glutathione peroxidase, several papers have appeared in literature claiming its biological activities. It was the subject of several clinical trials and it is currently in clinical evaluation for the treatment of COVID-19 patients. Given our interest in the synthesis and pharmacological evaluation of selenorganic derivatives with this review, we aimed to collect all the papers focused on the biological evaluation of ebselen and its close analogues, covering the timeline between 2016 and most of 2021. Our analysis evidences that, even if it lacks specificity when tested in vitro, being able to bind to every reactive cysteine, it proved to be always well tolerated in vivo, exerting no sign of toxicity whatever the administered doses. Besides, looking at the literature, we realized that no review article dealing with the synthetic approaches for the construction of the benzo[d][1,2]-selenazol-3(2H)-one scaffold is available; thus, a section of the present review article is completely devoted to this specific topic.

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Section: Anti-neurodegenerative Disordersmentioning

confidence: 99%

Ebselen and Analogues: Pharmacological Properties and Synthetic Strategies for Their Preparation

2021

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“…19,20 Multitarget drugs have been designed not only to treat kidney disease but also combat diabetes, metabolic disease, and hypertension at the same time. 23,24 This has been achieved by initially comparing multitarget drugs to the respective single-target approach in enzymatic or cell-based systems. 23,24 Because the target combinations for CKD involve individual targets that are expressed in different tissues of the body, an in vivo approach is required for validation of an anti-CKD multi-target drug.…”

Section: Progress With Multi-target Drugs For Kidney Diseasesmentioning

confidence: 99%

Multi-Target Drugs for Kidney Diseases

2021

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Kidney diseases such as acute kidney injury (AKI), chronic kidney disease (CKD), and glomerular nephritis can lead to dialysis and the need for kidney transplantation. The pathologies for kidney diseases are extremely complex, progress at different rates, and involve several cell types and cell-signaling pathways. Complex kidney diseases require therapeutics that can act on multiple targets. In the past ten years, in silico design of drugs has allowed for multi-target drugs to go quickly from concept to reality. Several multi-target drugs have been successfully made that target arachidonic acid pathways and transcription factors to treat inflammatory, fibrotic, and metabolic diseases. Multi-target drugs have also demonstrated great potential to treat diabetic nephropathy and fibrotic kidney disease. These drugs act by decreasing renal transforming growth factor-β (TGF-β) signaling, inflammation, mitochondrial dysfunction, and oxidative stress. There are several other recently developed multi-target drugs that have yet to be tested for their ability to combat kidney diseases. Overall, there is excellent potential for multi-target drugs that act on several cell types and signaling pathways to treat kidney diseases.

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“…A commonly used abbreviation is DMLs [designed multiple ligands; Morphy et al., ]. Examples of the successful development of DMLs remain rare [Gattrell et al., ], most likely because of the challenges in lead identification and optimization of such drugs. If the targets are unknown, lead identification can be done via phenotypic screening.…”

Section: Finding Drugs For Disease Network: Which Drugs Are Needed?mentioning

confidence: 99%

“…Merging pharmacophores seems to be a more promising approach. Examples of the design of DMLs for various disease states can be found in the literature [Morphy and Rankovic, ; Cavalli et al., ; Gattrell et al., ]. The subsequent optimization of a DML with regard to a balanced selectivity profile at the targets, in addition to a good pharmacokinetic profile, may be the even more challenging step [Morphy, ].…”

Section: Finding Drugs For Disease Network: Which Drugs Are Needed?mentioning

confidence: 99%

Biological Networks and Drug Discovery—Where Do We Stand?

Geppert

Koeppen

2014

Drug Development Research

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The progress in genomics and molecular biology during the last decade has led to the insight that complex diseases are caused by defects in many genes and that cellular processes are organized in complex networks. In the search of new drugs, these findings have not yet been fully taken into account. The currently predominating drug discovery approach in pharmaceutical industry is still target-centric, with the goal to optimize compounds toward high affinity and selectivity for a specific target. There is growing evidence that the successful development of effective disease-modifying medications needs a network approach instead. This might also help to reduce the very high failure rate in the current drug development process. This review outlines concepts and applications of network biology and routes toward drugs that are designed to interact with several targets. Obstacles to the implementation of this approach in the pharmaceutical industry are discussed.

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Designed multiple ligands in metabolic disease research: from concept to platform

Cited by 19 publications

References 16 publications

Ebselen and Analogues: Pharmacological Properties and Synthetic Strategies for Their Preparation

Ebselen and Analogues: Pharmacological Properties and Synthetic Strategies for Their Preparation

Multi-Target Drugs for Kidney Diseases

Biological Networks and Drug Discovery—Where Do We Stand?

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