Methods for the synthesis of macrocycle libraries for drug discovery

Terrett, N.K.

doi:10.1016/j.ddtec.2010.06.002

Cited by 52 publications

(33 citation statements)

References 27 publications

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“…4, 10–13 A second successful method utilizes computational and experimental high-throughput and fragment-based screening strategies to locate small molecule fragments that stick to protein surfaces. 14–19 Strategies that afford scaffolds for PPIs based on natural products and natural product like molecules, 20 peptide macrocycles 21 and phage display-based miniproteins 22–24 have also led to significant success. Although, PPIs cover large surface areas, often, a small subset of residues (termed “hot spot residues”) contributes significantly to the binding free energy.…”

Section: A Secondary Structure-centric View Of Protein Interfacesmentioning

confidence: 99%

Plucking the high hanging fruit: A systematic approach for targeting protein–protein interactions

Raj

Bullock

Arora

2013

Bioorganic & Medicinal Chemistry

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Development of specific ligands for protein targets that help decode the complexities of protein-protein interaction networks is a key goal for the field of chemical biology. Despite the emergence of powerful in silico and experimental high-throughput screening strategies, the discovery of synthetic ligands that selectively modulate protein-protein interactions remains a challenge for bioorganic and medicinal chemists. This Perspective discusses emerging principles for the rational design of PPI inhibitors. Fundamentally, the approach seeks to adapt nature’s protein recognition principles for the design of suitable secondary structure mimetics.

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Section: A Secondary Structure-centric View Of Protein Interfacesmentioning

confidence: 99%

Plucking the high hanging fruit: A systematic approach for targeting protein–protein interactions

Raj

Bullock

Arora

2013

Bioorganic & Medicinal Chemistry

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“…It may be possible that molecules that strictly obey the Ro5 may not be sufficient to interact with challenging targets. A number of groups are pursuing difficult drug targets using 'non-traditional' drug molecules such as macrocycles [75], stapled peptides [76] and diversity-oriented synthesis [77]. As we gain a better understanding of the factors influencing the bioavailability of these molecules, we will hopefully be able to derive guidelines that are similar in spirit to the Ro5.…”

Section: Expert Opinionmentioning

confidence: 97%

Going further than Lipinski's rule in drug design

Walters¹

2012

Expert Opinion on Drug Discovery

191

110

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While Lipinski's publication of the Ro5 and subsequent work by other authors has made medicinal chemists more aware of the relationships between physical properties and ADMET, it has hardly been a panacea. Pharmaceutical productivity continues to lag, and the industry is exploring new models to improve its output. If we are to progress, we need to move beyond simple models based on lipophilicity and gain a deeper understanding of molecular interactions.

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“…Hence, the dipeptide portion was coupled to the alkylated amino acid component under standard conditions to provide the protected linear precursor 267 (bond formation site indicated), containing all the necessary structural features and functionality of the target molecule. Simultaneous deprotection of the two terminal groups was followed by cyclization, for which the DEPBT (3-(diethoxyphosphoryloxy)-3H-benzo[d] [1,2,3]triazin-4-one) reagent of Goodman 351 gave the best results. A crystallization sequence led to ulimorelin (268) as the monohydrochloride monohydrate salt in very good overall yield and 99.7% purity.…”

Section: Synthesis At Scalementioning

confidence: 99%

“…(1) availability of a myriad of reaction conditions and reagents; (2) wellestablished chemistries that do not require special techniques; (3) flexibility for investigation of different sites of ring closure; and (4) facile execution on resin supports as would be advantageous for diversity investigations.…”

Section: Substitution Chemistrymentioning

confidence: 99%

The Synthesis of Macrocycles for Drug Discovery

Peterson¹

2014

Macrocycles in Drug Discovery

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Despite the attractive nature of macrocyclic compounds for use in new pharmaceutical discovery, applications have been hindered due to the lack of appropriate synthetic methods, in particular for the construction of libraries of such molecules. However, over the last decade, a number of effective and versatile methodologies suitable for macrocyclic scaffolds have been developed and applied successfully. These include classical coupling and substitution reactions, ring-closing metathesis (RCM), cycloaddition (“click”) chemistry, multicomponent reactions (MCR), numerous organometallic-mediated processes and others. This chapter presents a comprehensive compilation of these strategies and provides examples of their use in drug discovery, along with a description of those approaches that have proven effective for the assembly of macrocyclic libraries suitable for screening.

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Methods for the synthesis of macrocycle libraries for drug discovery

Cited by 52 publications

References 27 publications

Plucking the high hanging fruit: A systematic approach for targeting protein–protein interactions

Plucking the high hanging fruit: A systematic approach for targeting protein–protein interactions

Going further than Lipinski's rule in drug design

The Synthesis of Macrocycles for Drug Discovery

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