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Evaluation Models for Drug Transport Across the Blood–Brain Barrier
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
In vitro models find a suitable role in new drug research and development process which includes various stages like target identification, hit identification, lead identification, and finally optimization of the product. The first stage involves screening numerous compounds by high throughput screening when a target is identified. Simple models like monolayer and co-culture models are mainly used in the first step. The validation of identified compound and SAR are usually carried out in optimization stage which utilizes in vitro models like static co-culture and dynamic models that are sensitive to in vivo conditions. The correlation with human cells is required to be carried out to avoid interspecies variability at various stages of development (Paradis et al., 2016).
Key Concepts in Assay Development, Screening and the Properties of Lead and Candidate Compounds
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
A Hit molecule identified from a biological screen may not always be a suitable basis for a medicinal chemistry optimisation programme. The purpose of the Hit-to-Lead phase is to identify one or more molecules upon which such an optimisation could be successful (Bruno et al. 2017, Dinges et al. 2016, Gao et al. 2018b). Thus, the first part of this phase involves the validation of the Hit compounds in terms of confirming chemical structure and purity. This will usually involve a re-synthesis of the most interesting Hit compounds. Once Hit validation has been completed, analogues of the most promising Hit molecules are investigated, in terms of biological activity, selectivity and drugability in order to identify one or more high quality molecules that meet agreed pre-defined criteria. The typical information required for a Lead compound is summarised in Table 1.
A patent review of aldosterone synthase inhibitors (2014-present)
Published in Expert Opinion on Therapeutic Patents, 2022
This review provides an update on patent applications filed between January 2014 and March 2021 that claim new compounds for the inhibition of aldosterone synthase. Patents covering ASI prior to this timeline have been previously summarized in the literature [38]. The general formulas from each patent are presented to illustrate key structural features and inhibition activity against human and cynomolgus monkey CYP11B2/CYP11B1, along with the potency and selectivity of the compounds. In addition, the potential heme-binding scaffolds which facilitate the binding of iron are marked in red in each structure. In some cases, the hit identification, lead optimization strategies and preclinical studies for the key compounds are also highlighted. Patents filed during the reviewed time period are classified alphabetically by company name.
An overview of late-stage functionalization in today’s drug discovery
Published in Expert Opinion on Drug Discovery, 2019
Michael Moir, Jonathan J. Danon, Tristan A. Reekie, Michael Kassiou
The development of a drug is a lengthy and expensive process. The rising cost of development and low approval rates has meant that pharmaceutical companies are looking to implement changes that streamline development processes and increase output [10]. A significant stage in the drug discovery process is hit-to-lead and lead compound optimization. Optimization of a hit to a lead candidate can take pharmaceutical companies several years and cost over half a billion dollars (around a third of the total cost) [11]. Novel synthetic methodologies that expedite the synthesis of analogue libraries have the potential to alleviate this bottleneck. In their recent review, Boström and coworkers highlight the synthetic chemistry used for hit and lead optimization efforts is generally dominated by a few known, robust reactions [2]. Reliable late-stage functionalization methodologies represent an opportunity to expand the medicinal chemists’ toolbox and in turn increase the chemical space explored in drug discovery efforts.
Is drug repurposing really the future of drug discovery or is new innovation truly the way forward?
Published in Expert Opinion on Drug Discovery, 2021
Today, de novo drug discovery process affords important differences with the aforementioned strategy (Figure 1), not only in terms of time and cost but also from the innovation point of view. In traditional drug discovery, the first step in the process is hit identification that moves forward to a subsequent hit-to-lead step to extensively search the optimized candidate for further pharmaceutical development. In this step not only increase in target potency and selectivity is noted for but also drug-like properties. The in-depth study around the biological mechanism of action of the hits also provides new therapeutic classes. Early preclinical and clinical assessment will confirm this new drug ready to start studies in patients.