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Drug Design, Synthesis, and Development
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Understanding organic reaction mechanisms and the step-by-step processes by which molecules can be combined and altered enables chemists to design novel compounds. This is of fundamental importance to drug discovery because new drug molecules can be rationally designed to interact with a biological target associated with a disease and therefore have a biological effect that improves the condition of the patient. Subtle modification of molecular structures and lead compound optimisation can be done by implementing techniques in organic synthesis to yield the best possible drug properties of a lead compound. A key example of where this is important is asymmetric synthesis, where a stereospecific drug-target interaction is required, which could otherwise lead to side effects; note the case of thalidomide. While it is imperative to synthesise drugs with the least possible side effects, it is also essential to ensure the purity of drugs. This is the role of the analytical chemist, who has the important occupation of screening for and eliminating contaminants. Analytical techniques have improved greatly in modern times; contaminants can be traced below nano-gram levels, and methods such as spectroscopic techniques can be used to characterise the contaminants. As technologies advance in the future, medicinal chemists will be well equipped to manage the challenges that are presented to the field of medicine in the coming decades.
Pharmogenology: The Industrial New Drug Development Process
Published in Gary M. Matoren, The Clinical Research Process in the Pharmaceutical Industry, 2020
The Biological Lead Compound becomes the subject of intense investigation by the scientists in the drug disposition and metabolism disciplines. The use of a radiolabeled compound in animal studies at an early stage in development of the Biological Lead Compound facilitates an early and economical appreciation of the degree and rate of absorption of the drug and an indication of possible metabolism (10). An elimination or balance study is done in the rat and the dog and is designed to determine the comparative extent and routes of drug elimination after oral and intravenous administration of labeled compound. The amount of radioactivity eliminated in the urine and feces, as well as respiratory 14CO2, is determined. An estimate can be made of the degree of oral absorption of the compound by comparing the radioactivity detected in the urine of animals dosed intravenously or dosed orally. Using radiolabeled drug, the distribution of radioactivity in the various tissues of animals after oral administration of compound is also commonly studied. This distribution is measured at various periods of time after dosing to determine the tissue elimination kinetics of radiolabel and to determine whether radioactivity (unchanged drug and its metabolites) is concentrated in any tissue.
Swarm Intelligence and Evolutionary Algorithms for Drug Design and Development
Published in Sandeep Kumar, Anand Nayyar, Anand Paul, Swarm Intelligence and Evolutionary Algorithms in Healthcare and Drug Development, 2019
The various phases of drug development are: Fine Lead Compounds: Use biological knowledge from genomics or proteomics to identify relevant drug target.Optimize Lead Compound: Test collection of compounds in cell based or similar essays and confirm activity.Perform Chemical Traits: Modify compounds to improve binding affinity and bio-availability to reduce toxicity.Identity Target Protein: Access whether compound is safe and effective.Market Drugs: Drugs are finally launched in the market [37].One of the classes of methods that has been used in the pharmaceutical industry for this purpose is evolutionary algorithm, which is found to be typically apt for such purpose in an evolutionary algorithm, which is found to be quite appropriate as the drug design is largely survival of the fittest compounds.
Avoiding hindsight in non-obviousness determination: case law review of pharmaceutical patents and guidance from the KSR v Teleflex decision
Published in Expert Opinion on Therapeutic Patents, 2021
Referring to the Supreme Court’s decision in KSR v Teleflex, the District Court applied the following considerations to its non-obviousness analysis in this case: 1. Post-KSR, a prima facie case of obviousness for a chemical compound still, in general, begins with the reasoned identification of a lead compound. The District Court further explained that a lead compound is ‘a compound in the prior art that would be most promising to modify to improve upon its activity and obtain a compound with better activity’ [33].2. Under the flexible nature of the obviousness inquiry, the reason or motivation to modify a lead compound may come from any number of sources and need not necessarily be explicit in the prior art [34].3. Under KSR predictability is a vital consideration in the obviousness analysis [11].
Boswellic acids: privileged structures to develop lead compounds for anticancer drug discovery
Published in Expert Opinion on Drug Discovery, 2021
Hidayat Hussain, Iftikhar Ali, Daijie Wang, Faruck L. Hakkim, Bernhard Westermann, Luay Rashan, Ishtiaq Ahmed, Ivan R. Green
For the development of a successful lead compound, its pharmacokinetic studies should be carried out accurately. Various studies have demonstrated that AKBA and KBA are exceptionally good lipophilic drugs that result in a decrease absorption via the GIT. Moreover, both these compounds have low oral bioavailability due to their lipophilic nature. The initial pharmacokinetic investigation has led to the finding that minimum concentrations of both KBA and AKBA were present in human plasma after administration of frankincense [28]. Among pentacyclic triterpenoids, BAs are characterized by poor water solubility along with having a highly lipophilic character (1og P = 7–10.3) [99]. Another study illustrated that the metabolic profiles of KBA in liver and in rat plasma were similar for both in vitro and in vivo investigations while the presence of AKBA was not detected. This study demonstrated that the administration step should be further investigated to enhance the bioavailability of boswellic acids and their synthetic derivatives [28,100].
Drug metabolic stability in early drug discovery to develop potential lead compounds
Published in Drug Metabolism Reviews, 2021
Siva Nageswara Rao Gajula, Nimisha Nadimpalli, Rajesh Sonti
Assessing a drug’s metabolic properties is one of the most crucial steps during the drug discovery and development process. All major pharmaceutical companies have introduced in vitro methods to predict the drug metabolic properties in the preclinical stage. Determining the metabolic stability of a lead compound helps develop the right drug candidate with optimized pharmacokinetics. Among all in vitro models, liver microsomes offer high-throughput screens and a well-defined in vitro- in vivo extrapolation. Furthermore, rapid and advanced improvements in the LC-MS/MS with novel analysis strategies provide more accurate and fast results. In summary, integrating these metabolic stability studies in the drug discovery process offers cost and time effectiveness for pharmaceutical industries to identify new potent and therapeutically active chemical entities.