Archive for the ‘Reviews’ Category

HOT: A critical assessment of modeling safety-related drug attrition

In this HOT perspective, Hasselgreen and co-workers at AstraZeneca R&D Mölndal, reflect on the tough crisis that has afflicted the pharmaceutical industry in recent years, where the increased R&D budgets have not translated into new valuable products. This review offers an excellent overview of aspects and practicalities involved in preclinical toxicity prediction and analysis. The authors inspect commonly used guidelines/rules in medicinal chemistry aimed at reducing toxicity wondering if a simple distinction between compounds that have safety liabilities and “clean” compounds really exists. And crucially, they reflect on the impact of applying such guidelines on compounds progressing to clinical phases or even further and becoming approved drugs.

A critical assessment of modeling safety-related drug attrition

A critical assessment of modeling safety-related drug attrition
Daniel Muthas, Scott Boyer and Catrin Hasselgren
DOI: 10.1039/C3MD00072A

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Methanocarba ring, the rigid ribose modification for purine and pyrimidine receptors

Methanocarba ring as a ribose modification in ligands of G protein-coupled purine and pyrimidine receptors: synthetic approachesRibose containing adenosine receptors (ARs) and P2Y receptors for purine and pyrimidine nucleotides are involved in and regulate a myriad of physiological processes throughout the body, and have become important pharmaceutical targets for treating a diverse number of chronic and acute diseases.

An approach to enhance the selectivity of these nucleoside and nucleotide derivatives is to make the ribose ring more rigid. This is achieved by using a methanocarba (bicyclo[3.1.0]hexane) ring system as a rigid substitution for ribose which maintains either a North (N) or South (S) conformation, preserving or enhancing the potency and/or selectivity for certain receptor subtypes.

This review from Dilip K. Tosh and Kenneth A. Jacobson of the National Institute of Diabetes and Digestive and Kidney Diseases summarises recent advances in the synthetic approaches to methanocarba derivatives in the context of their use as definitive pharmacological probes.

Methanocarba ring as a ribose modification in ligands of G protein-coupled purine and pyrimidine receptors: synthetic approaches
Dilip K. Tosh and Kenneth A. Jacobson
DOI: 10.1039/C2MD20348K

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Review – Prenyltransferase inhibitors: treating human ailments from cancer to parasitic infections

Farnesyltransferase inhibitors such as lonafarnib (shown in the image) may hold the key to the treatment of a variety of diseases ranging from cancer to progeria.

In this review, Mark D. Distefano and Joshua D. Ochocki from the University of Minnesota discuss the progression of farnesyltransferase inhibitor (FTI) development. from the initial studies focussing on cancer therapeutics through to the more recent use of prenyltransferase inhibitors in the treatment of various disorders, such as progeria, parasitic infections and hepatitis C & D.

Included in this review:

  • Prenyltransferase inhibitor development
  • Prenyltransferase inhibitors in cancer
  • Farnesyltransferase inhibitors in Hutchinson–Gilford progeria syndrome
  • Farnesyltransferase inhibitors in parasitic diseases
  • Prenyltransferase inhibitors in hepatitis
  • Other potential therapies using prenyltransferase inhibitors

Prenyltransferase inhibitors: treating human ailments from cancer to parasitic infections
Joshua D. Ochocki and Mark D. Distefano
Med. Chem. Commun.
DOI: 10.1039/C2MD20299A

You may also be interested in reading the MedChemComm reviews from 2012; we’ve collected them all together in one place for you to easily browse. Why not take a look?
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Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A2A receptor

This review from the MedChemComm New Talent themed issue covers one of the first successful examples of structure-based drug design for stabilised G protein-coupled receptors (GPCRs), focusing on the development of a pre-clinical candidate for the treatment of Parkinson’s disease using StaR® technology.

Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A2A receptor
Stephen P. Andrews and Benjamin Tehan
DOI: 10.1039/C2MD20164J

Stephen P. Andrews and Benjamin Tehan from Heptares Therapeutics Limited review the role the application of StaR® proteins plays in the discovery and development of new ligands for the adenosine A2A receptor (A2AR).

StaR® proteins are GPCRs which have had a small number of point mutations introduced to thermostabilise them. These proteins are stable in detergent micelles and are suitable reagents for use with X-ray crystallography, biophysical screening
techniques and fragment screening. These properties have enabled the application of biophysical screening techniques of ligand–receptor complexes and have facilitated their crystallisation, which has allowed true structure-based drug design on a GPCR to take place for the first time.

This review is separated into two main parts:

1) Applications of stabilised GPCRs
–    Describing the thermostabilisation process for generating StaR® proteins and, using A2AR as an example, considers the implications that this has on receptor conformation.

2) Structure-based drug design with StaRs®
–    Discussing how the application of techniques covered in the first part of the review aided in the optimisation of a hit A2AR antagonist which was identified by virtual screening of experimentally enabled homology models.

Read the complete review here…

and find more articles from our New Talent themed issue here…

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Emac – a comparative index for the assessment of macrocyclization efficiency

New drug design strategies are required that deliver agents possessing ‘small molecule properties’ but that also possess the ability to disrupt interactions between large protein surfaces in a similar manner to current protein-based therapeutics.

Macrocycle-based drug design represents a new and compelling strategy that could fulfil this need; however typical high-dilution macrocyclisation conditions are inefficient and impractical in a pharmaceutical setting from cost, capacity and green chemistry perspectives.

In this review James C. Collins and Keith James from the Scripps Research Institute critically analyse macrocyclization reactions published over the last three years. Based upon on this analysis, and first-hand experience of macrocyclization, Collins and James propose a macrocyclization efficiency index, Emac, as a means of determining the true efficiency of a macrocyclization reaction.

Emac takes into account both reaction yield and concentration, which Collins & James state addresses the key factors that determine the practicality of using a given reaction in a drug discovery context. In other words, the Emac for a reaction indicates the likelihood of being able to conduct the reaction on a sufficiently large scale whilst remaining resource efficient.

This index also allows comparison of a large number of literature macrocyclization reactions and identifies those which deliver the powerful combination of high yield and high practicality. Collins and James hope that those who are actively engaged within the macrocyclization community will calculate the Emac for their reactions and report it in their publications, allowing the synthesis community to place the reaction within the context of the framework they outline in the review.

To read more about this index download the review today.

Emac – a comparative index for the assessment of macrocyclization efficiency
James C. Collins and Keith James
DOI: 10.1039/C2MD20176C
From the collection: The space in-between small molecules and biologicals

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Diaryl ether derivatives as anticancer agents – a review

This review article from Florence Bedos-Belval and co-workers at Université Paul Sabatier examines the possibility of diaryl ethers as a promising frame to design new anti-cancer agents.

Bedos-Belval et al. examine the diaryl ether scaffold found in natural products, related analogs and innovative molecules. Included in this examination is:

–    A look at encompassing synthesis,
–    Structure–activity relationships (SARs),
–    Studies on the biological action, namely in the context of anti-cancer activity.

Bedos-Belval et al. aim for this review is to show that the diaryl ether scaffold is an invaluable structure for the design of anticancer drugs.

Curious about diaryl ethers as anticancer agents? Read the full review today.

Diaryl ether derivatives as anticancer agents – a review
Florence Bedos-Belval, Anne Rouch, Corinne Vanucci-Bacqué and Michel Baltas
DOI: 10.1039/C2MD20199B

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Understanding the stereochemistry of polyketide biosynthesis

Complex polyketides are a pharmaceutically important group of natural product compounds which present an elaborate stereochemistry, set up  by ketoreductase enzymes that can control the the orientation of the substituents during polyketide biosynthesis. 

One of the challenges ahead is the reliable engineering of modular polyketide synthases to produce new polyketides for drug development.

In this review, Jianting Zheng and Adrian Keatinge-Clay present a summary of the recent advances in understanding the stereocontrol of ketoreductases in modular polyketide synthases from biochemical, engineering and structural studies, providing a critical view on the mechanisms of ketoreductase stereocontrol. This timely review covers a number of outstanding questions surrounding their selectivity, activity, and engineering potential.

Curious? Why not read it now:

The status of type I polyketide synthase ketoreductases
Jianting Zheng and Adrian T. Keatinge-Clay
Med. Chem. Commun., 2012, Advance Article
DOI:10.1039/C2MD20191G, Review Article
From collection New Talent

This review is part of MedChemComm’s New Talent themed issue

Highlighting medicinal chemistry research in its broadest sense and showcasing the strength of research being carried out by tomorrow’s leaders in the field: view the collection grow

Interested in the Structural Aspects of Biosynthesis?

Why not view our sister journal Natural Product Reportsthemed issue on the topic.
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Approaches to discover non-ATP site kinase inhibitors – a review by Lori Krim Gavrin

Major challenges currently exist in kinase research, such as being able to achieve selectivity between the large numbers of similarly structured family members all processing the same substrate. In addition to requiring this selectivity, ATP site inhibitors must also bind tightly to the kinase catalytic centre to overcome the high physiological concentration of ATP in the cell. And, as many ATP competitive scaffolds have already been discovered, the development of novel ATP site inhibitors is becoming increasingly more difficult.

In order to overcome these challenges and develop compounds with better selectivity among kinases, great interest is being paid to inhibitors that bind outside the ATP site. In this review Lori Krim Gavrin and Eddine Saiah, Pfizer, highlight the most commonly used methods to discover Type III (small molecule inhibitors that exclusively bind in a pocket adjacent to the ATP site) and IV kinase inhibitors (those that bind to a site remote from the ATP binding pocket). Included in the review are discussions on:

Screens to identify non-ATP site kinase binders
-Computational methods to identify non-ATP site kinase binders
-Small molecule spin-labeled probes to identify non-ATP site kinase binders

This review is part of MedChemComm’s New Talent themed issue; read the full article and visit the MedChemComm webpage to see other articles from this collection.

Approaches to discover non-ATP site kinase inhibitors
Lori Krim Gavrin and Eddine Saiah
DOI: 10.1039/C2MD20180A

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Review: Amino-derivatives of the sesquiterpene lactone class of natural products as prodrugs

The sesquiterpene lactone class of natural products displays a diverse array of biological activities due to the presence of the α-methylene-γ-lactone motif.  One of the limitations of is the intrinsic reactivity of the α-methylene-γ-lactone- motif which represents an electrophilic Michael acceptor that reacts with thiol nucleophiles and leads to undesired and toxic side effects

This review by David A. Colby et al. provides an interesting overview about an emerging prodrug approach that has been developed to overcome these problems in which an amine is added into the α-methylene-γ-lactone to mask this group from nucleophiles and increase solubility.

Included is a concise description of the medicinal chemistry of amino-derivatives of the sesquiterpene lactones, from early development in synthesis, to application in medicinal chemistry, to its move to a clinical candidate.

For the complete picture on this prodrug approach download the review now by following the link below…

Amino-derivatives of the sesquiterpene lactone class of natural products as prodrugs
James R. Woods, Huaping Mo, Andrew A. Bieberich, Tanja Alavanja and David A. Colby
DOI: 10.1039/C2MD20172K

The review features as part of MedChemComm’s New Talent issue; view the expanding collection of articles for this issue HERE
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Recent applications of multicomponent reactions in medicinal chemistry

Multicomponent reactions (MCRs) are defined as being a one-pot process that involves the reaction of at least three components to form a single product that retains the majority of the atoms from the starting materials.

These reactions are atom economic, step efficient, and owing to their flexibility, have found applications in many fields of medicinal chemistry, such as cancer therapy and infectious diseases, where MCRs are powerful tools for drug discovery and development. The application in these fields is quite broad, ranging from initial lead structure identification to the generation of large libraries of analogues.

In this Review Romano V. A. Orru and colleagues from VU University Amsterdam highlight recent applications (2005-present) of multicomponent reactions in medicinal chemistry, discussing these applications by therapeutic field.

Read the full review…. Here

Recent applications of multicomponent reactions in medicinal chemistry
Paul Slobbe, Eelco Ruijter and Romano V. A. Orru

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