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Building Blocks

Macro Space: the REAL Space of macrocycles

Macro_Space

As I already wrote in my previous post, we at Enamine are constantly working on extending our REAL concept (where REAL is for REadily AccessibLe compounds). Basically, this concept allows for the generation of a virtual chemical space based on the experimentally validated synthetic accessibility. Until now the REAL Space has comprised 15.5 billion make-on-demand molecules and is currently the largest offer of commercially available compounds. It was shown that this chemical space is especially useful in combination with high-throughput virtual screening techniques (see Nature 2019, 566, 224–229 and Nature 2020, 580, 663–668); there is also a number of other ways to access it.

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REAL Space rapidly expands

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More than a decade ago, we have launched an in-house project on the generation of a virtual compound database based on the experimentally validated synthetic accessibility (the so-called REAL Database, where REAL is for REadily AccessibLe). Further extension of this concept led to the development of REAL Space, a searchable chemical space that is not typically stored as an enumerated database but generated upon query through chemoinformatics software. Until now the largest REAL Space has comprised 15.5 billion make-on-demand molecules and is currently the largest offer of commercially available compounds. Recently, utility of the REAL methodology was confirmed by discovery of highly potent AmpC β-lactamase inhibitors, D4 dopamine receptor ligands, and Kelch-like ECH-associated protein 1 (KEAP1) inhibitors published in Nature (see Nature 2019, 566, 224–229 and Nature 2020, 580, 663–668).

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A housane that our chemists built

Housane-News

A diastereoselective approach to cis- and trans-1,3-disubstituted bicyclo[2.1.0]pentanes (housanes) was recently reported by our chemists in The Journal of Organic Chemistry. The article included preparation of 35 derivatives on up to 100 g scale. Moreover, pKa’s and conformational features of selected examples of housanes (e.g. GABA analogues) were also studied and compared to that of the corresponding 1,3-disubstituted cyclopentanes. For an extended list of novel housanes check the Enamine Store page.

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Paper by Enamine chemists is featured on the JOC cover

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In a recent JOC paper, Enamine chemists reported a comprehensive study of regioselective [3 + 2] cycloaddition reactions – an efficient approach towards 3,5-disubstituted isoxazole building blocks bearing mono-, di- or trifluoromethyl substituents. More than 100 derivatives were obtained on up to 130 g scale, and multigram quantities of representative examples are available from EnamineStore at the isoxazole library.

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Introducing alkyl substituent into the piperidine core goes multigram

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Enamine’s EurJOC paper on the scalable and regioselective preparation of all isomeric (cyclo)alkyl piperidines and the corresponding amino alcohols was featured on the cover of the issue. The multigram quantities of these derivatives are available from EnamineStore at the piperidine library

 

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A New Paper by Enamine’s Scientists: "Synthesis and chemical transformations of diazolyl α,α-difluoroacetates"

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Recent Enamine’s paper disclosed novel heteroaryl difluoroacetates and the corresponding carboxylic acids, amides, nitriles and alcohols as promising building block in drug design. Known literature example of metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitor 1 led to the the corresponding 2,2-difluoro-2-pyridin-2-yl derivative 2, which is not prone to metabolic oxidation at the α-methylene group next to the aromatic moiety.

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A New Review Paper by Enamine’s Scientists: "The Symbiotic Relationship Between Drug Discovery and Organic Chemistry”

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The review mentioned in the title was published in Chemistry – A European journal and emerged from a collaboration of scientists from Enamine Ltd. (including myself) and Duncan Judd from Awridian Ltd. Despite some “symbiotic” hype in the title (as it was pointed out by one of the reviewers), the paper provides a comprehensive overview of concepts which appeared at the edge of these disciplines recently. Initially, we have aimed at tutorial review that might help synthetic chemists to become familiar with state-of-the-art in the field. Thus, genesis of concepts like “…-oriented” syntheses (DOS, LOS, BIOS, FOS, DTS), as well as related “abbreviated” strategies (BBs, FBDD, DEL, REAL) has been discussed, together with recent advances focusing mainly on chemical aspects.

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"Hot"​ Research Areas in Drug Discovery -- 2019

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Things like gene editing, stem cells, immunotherapies and new types of biologics are now mega-trends in the pharmaceutical industry, widely covered in media, and I guess there is little doubt that biology is the next big thing in medicine. However, in this post I would like to outline several promising areas in small molecule drug discovery, suggesting a lot of untapped potential and investment prospects in this more “traditional” pharmaceutical research space.

 

1.Targeting ribonucleic acid (RNA)

 

The majority of existing marketed drugs out there are designed to somehow modulate proteins in the body, thereby disrupting a disease progression. However, going one step back and trying to disrupt a pathological process earlier -- right before a protein is actually made in the body -- seems a powerful concept. This can be achieved by influencing ribonucleic acid (RNA), a central actor molecule in the process of gene expression -- the one leading to the formation of proteins as instructed by the human genome.

 

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New Building Blocks For Drug Discovery Are Getting Closer: Gem-difluorocyclopropane-derived Amines

Artwork by Web Design Studio "ZORELiT"

(This article originally appeared at Sciencetrends.com)

 

Modern drug discovery relies heavily on the ability of chemists to produce good starting points for producing high-quality lead compounds. Several concepts were established in the last two decades to aim synthetic organic chemistry onto the proper areas of chemical space, in particular, the so-called lead-oriented approach which describes paradigm shift towards low-molecular-weight, relatively hydrophilic, conformationally restricted, sp3-enriched structures.

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Hunting For New Drug Discovery Ideas In The CLOUD

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Patient diversity and developing drug resistance can undermine the efficiency of existing therapies in a long-term pharmacological treatment of diseases, such as cancer and infections.

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Expanding Horizons for Fragment Based Drug Discovery (FBDD)

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Scientists estimated that the human genome encodes above 20,000 different proteins in our body. However, available public databases contain records of known ligands for only about 10% of all proteins. The rest of proteins remains either not yet properly explored, or is labelled “undruggable”.

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