The influence and manipulation of acid/base properties in drug discovery
Publication date: Available online 26 April 2018Source: Drug Discovery Today: TechnologiesAuthor(s): David T. Manallack, Elizabeth Yuriev, David K. ChalmersThere is a growing awareness of the importance of acid/base properties in medicinal chemistry research. In many drug classes, ionisable groups are present that make critical interactions with the receptor and are essential for potency. Yet the presence of these groups may cause problems with oral bioavailability, pharmacokinetics, or toxicity. Manipulating pKa values during drug development or applying pro-drug techniques are strategies that can overcome potential defic...
Source: Drug Discovery Today: Technologies - July 10, 2018 Category: Drugs & Pharmacology Source Type: research
Different types, applications and limits of enabling excipients of pharmaceutical dosage forms
Publication date: Available online 30 April 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Barnabás Palcsó, Romána ZelkóAlong with the development of novel drug delivery systems the material science is also advancing. Conventional and novel synthetic or natural excipients provide opportunities to design dosage forms of the required features including their bioavailability. Emerging trends in the design and development of drug products indicate an increasing need for the functionality-related characterization of excipients. The purpose of this review is to provide an overview of different types of excipients i...
Source: Drug Discovery Today: Technologies - July 10, 2018 Category: Drugs & Pharmacology Source Type: research
Automated techniques in pKa determination: Low, medium and high-throughput screening methods
Publication date: Available online 10 May 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Christophe DardonvilleDrug discovery programs that generate hundreds of new molecular entities need efficient methodologies for physicochemical profiling. Several high-throughput methods for pKa screening have been developed in the last 15 years to determine this key physicochemical parameter. Separation techniques such as HPLC–MS or capillary electrophoresis are particularly well-suited due to their high throughput and capacity to deal with impure or complex samples. In addition, potentiometric and (mostly) UV-metric-based...
Source: Drug Discovery Today: Technologies - July 10, 2018 Category: Drugs & Pharmacology Source Type: research
Automated assays for thermodynamic (equilibrium) solubility determination
Publication date: Available online 23 May 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Tomás Sou, Christel A.S. BergströmSolubility is a crucial physicochemical property for drug candidates and is important in both drug discovery and development. Poor solubility is detrimental to absorption after oral administration and can mask compound activity in bioassays in various ways. Hence, solubility liabilities should ideally be identified as early as possible in the drug development process. With the increasing number of compounds as potential drug candidates, automated thermodynamic solubility assays for high thr...
Source: Drug Discovery Today: Technologies - July 10, 2018 Category: Drugs & Pharmacology Source Type: research
CRISPR/Cas9 genome surgery for retinal diseases
Publication date: Available online 18 June 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Christine L. Xu, Karen Sophia Park, Stephen H. TsangRetinal diseases that impair vision can impose heavy physical and emotional burdens on patients’ lives. Currently, clustered regularly interspaced short palindromic repeats (CRISPR) is a prevalent gene-editing tool that can be harnessed to generate disease model organisms for specific retinal diseases, which are useful for elucidating pathophysiology and revealing important links between genetic mutations and phenotypic defects. These retinal disease models are fundamenta...
Source: Drug Discovery Today: Technologies - July 10, 2018 Category: Drugs & Pharmacology Source Type: research
Brief overview of solubility methods: Recent trends in equilibrium solubility measurement and predictive models
Discussion of experimental and computational methods: was based on relevant industrial references. (Source: Drug Discovery Today: Technologies)
Source: Drug Discovery Today: Technologies - July 10, 2018 Category: Drugs & Pharmacology Source Type: research
CRISPR/Cas9-mediated genome editing in human stem cell-derived cardiomyocytes: Applications for cardiovascular disease modelling and cardiotoxicity screening
Publication date: Available online 25 June 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Effimia Christidi, Haojun (Margaret) Huang, Liam R. BrunhamCardiovascular diseases (CVDs) are leading causes of death worldwide, and drug-induced cardiotoxicity is among the most common cause of drug withdrawal from the market. Improved models of cardiac tissue are needed to study the mechanisms of CVDs and drug-induced cardiotoxicity. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CM) have provided a major advance to our ability to study these conditions. Combined with efficient genome editing technologies, such a...
Source: Drug Discovery Today: Technologies - July 10, 2018 Category: Drugs & Pharmacology Source Type: research
Experimental and pKa prediction aspects of tautomerism of drug-like molecules
Publication date: Available online 27 June 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Yvonne Connolly MartinMolecules that can tautomerize are a challenge to scientists because one must consider the possible tautomers in most tasks involving chemical structures: for example, searching databases, interpreting experimental property measurements, calculating properties, virtual screening, and analyzing structure-bioactivity relationships. The challenge in interpreting property measurements such as pKa values feeds into the general lack of extensive information not only of the relative tautomer stability in water...
Source: Drug Discovery Today: Technologies - July 10, 2018 Category: Drugs & Pharmacology Source Type: research
Physico-chemical characterization of self-emulsifying drug delivery systems
The objective of this study was to summarize these physicochemical factors characterized SEDDS. Determination of self-emulsification process and ternary phase diagram are the basis of preparations. The position of APIs in SEDDS inclusion can be determined by dye solubilisation test. The end point of self-emulsification was controlled by turbimetric evaluation. Optimisation of droplet size and zeta potential are crucial parameters because they can influence i.e. the dissolution rate of APIs and the stability of SEDDS. Besides the basic methods in the characterization of SEDDS such as dispersibility tests, turbidimetric eval...
Source: Drug Discovery Today: Technologies - July 10, 2018 Category: Drugs & Pharmacology Source Type: research
Integrating biocatalysis and multicomponent reactions
Publication date: Available online 28 June 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Chiara Lambruschini, Andrea Basso, Luca BanfiWhile often multicomponent reactions (MCR) are used for the diversity-oriented synthesis of racemic (or achiral) molecular entities, this short review describes two alternative approaches for accessing enantiopure products exploiting the power of biocatalysis. Enzymes or microorganisms may be used for preparing enantiopure MCR inputs or for resolving racemic (or achiral) MCR adducts.Graphical abstract (Source: Drug Discovery Today: Technologies)
Source: Drug Discovery Today: Technologies - July 10, 2018 Category: Drugs & Pharmacology Source Type: research
Multi-component synthesis of fluorophores via catalytic generation of alkynoyl intermediates
Publication date: Available online 2 July 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Thomas J.J. MüllerThis account summarizes recent developments of aggregation-induced emissive and emission solvatochromic fluorophores by multicomponent reactions. Key intermediates are catalytically generated alkynoyl derivatives that are directly transformed into luminophores in a one-pot fashion. The conciseness in combination with ready access to tailored chromophore libraries makes this synthetic methodological concept superior over classical multistep syntheses.Graphical abstract (Source: Drug Discovery Today: Technologies)
Source: Drug Discovery Today: Technologies - July 10, 2018 Category: Drugs & Pharmacology Source Type: research
Arynes and isocyanides: Two close-knit partners in multicomponent reactions
Publication date: Available online 2 July 2018Source: Drug Discovery Today: TechnologiesAuthor(s): Marta Serafini, Tracey PiraliDespite benzyne has been known since 1940, this fascinating species has received much attention only over the last decades. The renaissance of interest in aryne chemistry is ascribable to the seminal discovery that arynes can be generated in situ from stable and commercially available precursors under mild and neutral conditions. Thanks to their high reactivity, arynes are key intermediates in countless chemical transformations ranging from cycloadditions to insertions and, among all these approac...
Source: Drug Discovery Today: Technologies - July 10, 2018 Category: Drugs & Pharmacology Source Type: research
Inflammation and DNA damage: Probing pathways to cancer and neurodegeneration
Publication date: November 2017Source: Drug Discovery Today: Technologies, Volume 25Author(s): Mehran Makvandi, Mark A. Sellmyer, Robert H. MachCancer and neurodegeneration represent two opposite ends of the biological spectrum but contain many common biological mechanisms. Two such mechanisms include the elevated levels of oxidative stress and DNA damage. In this brief review, we describe current approaches for imaging these biological pathways with the molecular imaging technique, Positron Emission Tomography (PET), and the potential of PET imaging studies to measure the efficacy of anticancer drugs and strategies for de...
Source: Drug Discovery Today: Technologies - July 6, 2018 Category: Drugs & Pharmacology Source Type: research
Use of carbon-11 labelled tool compounds in support of drug development
Publication date: November 2017Source: Drug Discovery Today: Technologies, Volume 25Author(s): Giulia Boscutti, Mickael Huiban, Jan PasschierThe pharmaceutical industry is facing key challenges to improve return on R&D investment. Positron emission tomography (PET), by itself or in combination with complementary technologies such as magnetic resonance imaging (MRI), provides a unique opportunity to confirm a candidate’s ability to meet the so-called ‘three pillars’ of drug development. Positive confirmation provides confidence for go/no-go decision making at an early stage of the development process and enables infor...
Source: Drug Discovery Today: Technologies - July 6, 2018 Category: Drugs & Pharmacology Source Type: research
Medicinal Chemistry strategies for PET tracer discovery
Publication date: November 2017Source: Drug Discovery Today: Technologies, Volume 25Author(s): José Ignacio Andrés, Mark SchmidtThe detection of gamma rays, resulting from decay of positron emitting isotopes, allows exquisitely sensitive detection of probes radiolabeled with such isotopes. These probes can be designed for high affinity binding to specific molecular targets and be used as tools in the early development of drugs, particularly for neuropsychiatric disorders. Availability of novel tracers requires dedicated resources and selection assays. Many of the selection assays are similar to those used for discovery o...
Source: Drug Discovery Today: Technologies - July 6, 2018 Category: Drugs & Pharmacology Source Type: research
