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Advanced Medicinal Chemistry-Safety Assessment PowerPoint Presentation

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Description : Check out this medical PowerPoint presentation titled "Advanced Medicinal Chemistry - Safety Assessment" by Rhona Cox.

This medical PowerPoint presentation tells us how safety assessment is a critical aspect of medicinal chemistry. The goal of safety assessment is to identify any potential risks associated with the use of a drug, both in terms of efficacy and toxicity, and to minimize these risks as much as possible. Safety assessment involves a range of activities, including preclinical testing, clinical trials, and post-marketing surveillance.

Preclinical testing involves a series of in vitro and in vivo experiments that are designed to evaluate the pharmacological properties of a drug candidate and to determine its safety profile. These tests are typically conducted in animal models, such as mice, rats, dogs, and monkeys. The tests are designed to evaluate the drugs pharmacokinetic properties, including absorption, distribution, metabolism, and excretion, as well as its pharmacodynamic properties, such as its mechanism of action and its potential for adverse effects.

Clinical trials are conducted to evaluate the safety and efficacy of a drug in humans. These trials are typically conducted in three phases, with each phase designed to evaluate different aspects of the drugs safety profile. Phase I trials typically involve a small number of healthy volunteers and are designed to evaluate the drugs pharmacokinetic properties and to identify any potential adverse effects. Phase II trials involve a larger number of patients and are designed to evaluate the drugs efficacy and to further assess its safety profile. Phase III trials involve a large number of patients and are designed to confirm the drugs efficacy and safety profile and to evaluate its long-term effects.

Post-marketing surveillance involves monitoring the safety of a drug after it has been approved for use. This involves tracking adverse events and monitoring drug interactions and other factors that may impact the drugs safety profile. Post-marketing surveillance is an ongoing process and is critical for identifying any potential safety issues that may arise over time.

In summary, safety assessment is a critical aspect of medicinal chemistry that involves a range of activities designed to evaluate the safety profile of a drug candidate. These activities include preclinical testing, clinical trials, and post-marketing surveillance, and are critical for ensuring the safety and efficacy of drugs for human use.

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Published on : Jun 23, 2023 | Views : 1027 | Downloads : 0

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Slide 1-

Advanced MedicinalChemistry Rhona Cox AstraZeneca R&D Charnwood Lectures 8 and 9: Safety Assessment
Slide 2-

Preclinical toxicology Before human studies, it is necessary to demonstrate safety in vitro and in vivo. These assumptions are broadly true, but despite this, we cannot be certain that a chemical will show no toxic effects in humans. We assume that in vitro assays predict in vivo effects the effects of chemicals in laboratory animals apply to humans the use of high doses in animals is valid for predicting possible toxicity in humans.
Slide 3-

Why do compounds still fail once they reach clinical trials? Only about 1 in 9 compounds going into Phase 1 clinical trials will become marketed medicines. We have improved our ability to predict pharmacokinetics in man since 1991. Now we need to improve our toxicology predictions. 1991 2000 Reasons for failure of medicines in clinical trials
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Toxic effects can include: Mechanism based pharmacology Formation of reactive metabolites Activation of other receptors, including hERG Interactions with other substances Idiosyncratic toxicity What do we already know about toxicity? N.B. Problems with toxicity (apart from those related to the target itself) can often be avoided by making a very potent compound. e.g. pIC50 (target) = 7.0, pIC50 (hERG) = 6.0, margin = 10-fold pIC50 (target) = 9.0, pIC50 (hERG) = 6.0, margin = 1000-fold
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Caused when activation of the target causes unwanted effects as well as the desired therapeutic effect. Balance of good/bad effects. Usually not predictable from in vitro tests, but can sometimes be predicted from animal models. A big potential problem with drugs designed for completely novel targets, rather than new drugs for a known mechanism. Mechanism-based pharmacology
Slide 6-

ß-agonists (e.g. salbutamol) are used to control asthma by causing activation of the ß2 receptors in the lung. This causes the airways to dilate. These compounds are taken by inhalation, so most of the drug stays in the lung. Case study: beta agonists salbutamol If the patient takes too much medicine, the levels in the systemic circulation rise and can now affect the ß2 receptors in the heart causing palpitations.
Slide 7-

We don’t want chemically reactive medicines! What functional groups might we want to avoid? e.g. These are all electrophiles, which means that they can covalently bind to nucleophiles in the body, e.g. in proteins and DNA which lead to toxic effects. Most common effects are hepatotoxicity (liver) & genotoxicity (DNA). But don’t forget that in the body, chemicals are metabolised so we need to consider the fate of our new medicine – will any of the metabolites be chemically reactive? Formation of reactive metabolites
Slide 8-

Some unwanted groups!
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Nitro Acylating agents Isocyanates Mono-substituted furans and thiophenes Alkylsuphohonate esters Anilines Electophilic aromatics Terminal acetylenes Electrophilic esters Michael acceptors Aziridines Epoxides Azo Masked anilines Disulphides Alkylhalides Chloroamines Certain phenols Hydrazines Some unwanted groups!
Slide 10-

Case study: paracetamol
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‘Ames’ test to detect mutagenicity Use a genetically modified bacterium which cannot grow in the absence of histidine. Expose bacteria to chemical. If the chemical can cause mutations, the genetic modification can be reversed and the bacteria will grow. Can also be carried out in the presence of liver enzymes to look for mutagenic metabolites. Avoiding the problem Most obviously, avoid functional groups known to show reactive metabolites (not an absolute – some are worse than others). Test for the presence of reactive groups Look for binding to proteins or glutathione - detect by mass spectroscopy glutathione
Slide 12-

Sometimes known as ‘off-target toxicity’. Screen against other systems – similar targets will be done early on in the project. Before nomination to preclinical studies, the compound will be tested in many other assays to look for activity. Potency (and therefore dose) is important as we are looking for a safety margin, i.e. the absolute potency at another receptor is less important than how much less than the potency at the primary receptor it is. Remember! If pIC50 (A) = 7.0 and pIC50 (B) = 6.0, the margin is 10x. But if pIC50 (A) = 9.0, the margin is 1000x. Activation of other receptors/enzymes
Slide 13-

hERG = ‘human ether-a-go-go related gene’ Potassium channel Activation causes prolongation of electrical impulses regulating heart beat Can lead to fatal arrhythmias hERG Q P S R T Q P S R T Normal heart beat Activation of hERG ‘T’ wave is delayed
Slide 14-

Lots of marketed drugs bind to it, with apparently diverse structures. e.g. grepafloxacin (antibiotic) Why is hERG important? terfenadine (antihistamine) astemizole (antihistamine) sertindole (neuroleptic)
Slide 15-

Lots of marketed drugs bind to it, with apparently diverse structures. e.g. grepafloxacin (antibiotic) Why is hERG important? terfenadine (antihistamine) astemizole (antihistamine) sertindole (neuroleptic)
Slide 16-

Lipophilic base, usually a tertiary amine X = 2-5 atom chain, may include rings, heteroatoms or polar groups Now we know about it, we can try and design hERG activity out and can test for activity in vitro. A hERG pharmacophore
Slide 17-

hERG IC50= 5800nM calculated pKa = 8.6 calculated logD = 0.3 hERG IC50= >50,000nM calculated pKa = 8.5 calculated logD = -3.3 Case study: farnesyltransferase inhibitors Changing the lipophilic aromatic ring to a polar one reduces hERG activity by >10x.
Slide 18-

Case study: farnesyltransferase inhibitors Synthesis of the first compound:
Slide 19-

It’s complicated enough to look at the pharmacokinetics, toxicology etc of one medicine at a time, but many patients take several medicines, which can interact…… What might cause this? One substance can affect the metabolism of another. This is why many medicines have a warning on them to say that the patient shouldn’t drink alcohol whilst taking the medication, because alcohol metabolism can affect drug metabolism. Drug-drug interactions (DDIs)
Slide 20-

Cytochrome P450 (CYP) Top 200 drugs in the USA in 2002 Primary route of clearance Primary metabolic enzymes So compounds which inhibit and induce CYPs have the potential to interact with many other drugs.
Slide 21-

Case study 1: terfenadine & ketoconazole Terfenadine – antihistamine drug on market for many years as an ‘over the counter’ remedy for hayfever. Found to cause life threatening cardiac arrhythmias when co-administered with medicines such as erythromycin (antibiotic) or ketoconazole (antifungal). Caused by inhibition of hepatic P450 enzymes. terfenadine ketoconazole
Slide 22-

Case study 1: terfenadine & ketoconazole Found that the major metabolite of terfenadine, caused by oxidation of the tert-butyl group, is the active species. This compound, fexofenadine, has little hERG activity as it is a zwitterion, and is now a medicine in its own right. terfenadine (hERG pIC50 ~ 7.6) fexofenadine hERG pIC50 ~ 4.8
Slide 23-

Case study 2: MAOIs and the ‘cheese effect’ Monoamine oxidase inhibitors (MAOIs) have antidepressant activity. Depressed individuals often have decreased levels of amines such as noradrenaline, serotonin and dopamine in the brain. MAOIs increases these levels by reducing oxidation of the amines. However, they are not the drug of choice as they are sometimes associated with cardiovascular side effects. noradrenaline (R = OH) dopamine ( R = H)
Slide 24-

Case study 2: MAOIs and the ‘cheese effect’ Side effects caused when patient has eaten food which contains high levels of tyramine, e.g. cheese, wine, beer. Ingested tyramine causes the release of noradrenaline (NA), which would normally be metabolised by MAOs. But because these enzymes have been inhibited, the NA levels rise. As NA is a vasoconstrictor, the blood pressure rises uncontrollably, which can trigger a cardiovascular event. tyramine (R = H) serotonin (R = OH) noradrenaline
Slide 25-

‘Idiosyncratic toxicity’ is something of a catch-all term to include other toxic effects that we don’t currently understand. Note that increased potency reduces the possibility of this. It is desirable to have two or more compounds in development which are structurally different – this reduces the possibility of both being hit by idiosyncratic toxicity problems. It’s a continuous challenge to understand the causes of idiosyncratic toxicity therefore to be able to avoid them at an early stage. Idiosyncratic toxicity