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2024‐01‐08 CHMI 4446 EL Drug Design and Development Winter 2024 1 What is a drug? Pharmaceutical agent Penicillin Heroin Good and bad drugs Therapeutic index Morphine Regulations and the Law Poisons and toxins Food Pesticides / herbicides Alcohol Cannabis Caffeine Selective toxicity 2 1 2024‐01‐08 F...

2024‐01‐08 CHMI 4446 EL Drug Design and Development Winter 2024 1 What is a drug? Pharmaceutical agent Penicillin Heroin Good and bad drugs Therapeutic index Morphine Regulations and the Law Poisons and toxins Food Pesticides / herbicides Alcohol Cannabis Caffeine Selective toxicity 2 1 2024‐01‐08 FDA Definition of a Drug 3 Scientific Disciplines involved in Drug Design and Development  Organic chemistry  Genetics  Physical chemistry  Cell biology  Pharmacology  Physiology  Biochemistry  Pathology  Molecular biology  Biophysics  Toxicology  Computation and Modeling 4 2 2024‐01‐08 Outline of the drug discovery and development process Although drug discovery and development is represented here as a continuous flow process (timeline), there are many iterative processes throughout (illustrated in the spiral representation as bridges). ADME = Absorption, distribution, metabolism, excretion 5 Stages of the Drug Design and the Development Process  Identification and validation of disease‐modifying targets (2 major strategies):  Molecular approach (focus on cells or cell components; use of clinical samples and cell models)  Systems approach (study of diseases in whole organisms)  Before or after target disease identification:      Selection of multidisciplinary research team Selection of a promising approach Budget decisions Chemistry: synthesis, collection of natural products Pharmacology: screening methods, assays 6 3 2024‐01‐08 Stages of the Drug Design and the Development Process (2)  First studies of initial classes of compounds in animals (potency, selectivity, toxicity)  Synthesis of most active compounds (after search of literature and patents)  More in‐depth pharmacology: mode of action, efficacy, acute and chronic toxicity, genotoxicity, ADME  Large‐scale synthesis and formulation studies  Application for patent protection  Very large‐scale synthesis (before or during clinical trials) Absorption, distribution, metabolism, excretion 7 Stages of the Drug Design and the Development Process (3)  Clinical trials:  Phase I: safety, dosage, blood studies on healthy individuals  Phase II: efficacy, side effect studies on a limited groups of patients  Phase III: efficacy, long‐term and rare side effects (studied with a large group of patients)  Regulatory review  Marketing  Distribution, advertisement Note 1 : Patent protection usually expires after 17‐25 years. Thus, the pharmaceutical company needs to recoup all the capital spent on research and development during this limited time period. Note 2: It is also clear that the later a project fails, the more expensive it is (it is advisable to foresee potential failures and road blocks as early as possible in the drug design process). 8 4 2024‐01‐08 Attrition during the drug development process Attrition: general reduction, weakening NDA = New drug application IND = Investigational new drug Only 1 out of 9,000 – 10,000 molecules make it to the drug market! 9 Drug discovery and development success rates Only 1 out of 24 early‐state programs (target‐to‐hit stage) will produce a marketable drug. The overall cost of developing a single new drug takes into account the costs of all unsuccessful programs. Years 10 5 2024‐01‐08 Top 10 drugs (in terms of sales in the US dollars) Drug name Manufacturer(s) 2022 Sales Indication(s) 1. Comirnaty COVID‐19 vaccine Pfizer/BioNTech $55,918,791,640 2. Humira (adalimumab) AbbVie $21,237,000,000 3. Keytruda (pembrolizumab) Merck $20,937,000,000 various cancers 4. Paxlovid Pfizer $18,933,000,000 prevention of severe COVID‐19 5. Spikevax COVID‐19 vaccine Moderna $18,435,000,000 reduce risk of COVID‐19 infection 6. Eliquis (apixaban) Bristol Myers Squibb and Pfizer $18,269,000,000 blood clots 7. Eylea (aflibercept) Regeneron Pharmaceuticals, Bayer $12,721,221,200 age‐related macular degeneration, macular edema and diabetic retinopathy 8. Biktarvy (bictegravir, emtricitabine, and tenofovir alafenamide) Gilead Sciences $10,390,000,000 HIV 9. Revlimid (lenalidomide) Bristol Myers Squibb (Celgene) $9,978,000,000 myelodysplastic syndrome, multiple myeloma, and mantle cell lymphoma 10. Stelara (ustekinumab) Janssen (Johnson & Johnson) $9,723,000,000 plaque psoriasis, psoriatic arthritis, ulcerative colitis and Crohn’s disease The COVID‐19 vaccine topped the list of 2022’s 50 best‐selling pharmaceuticals. It sold slightly more last year. rheumatoid and psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis From: https://www.drugdiscoverytrends.com/50‐of‐2022s‐best‐selling‐pharmaceuticals/ 11 R&D Expenditures in 2022: The Top 25 pharmaceutical companies From: https://www.drugdiscoverytrends.com /top‐pharma‐rd‐spenders‐2022/ 12 6 2024‐01‐08 Some R&D Expenditures in 2022 by percentage Company Total R&D spending (in USD) R&D spending as the percentage of total sales (%) Regeneron Pharmaceuticals 3,592,500,000 29.5 Vertex Pharmaceuticals 2,540,300,000 28.4 Boehringer Ingelheim 5,267,000,000 27.0 Eli Lilly 7,190,800,000 25.2 Merck & Co 13,548,000,000 22.9 AstraZeneca 9,762,000,000 22.0 Bristol Myers Squibb 9,509,000,000 20.6 Novartis 9,996,000,000 19.8 Moderna 3,295,000,000 17.1 Pfizer 11,428,000,000 11.4 From: https://www.drugdiscoverytrends.com/top‐pharma‐rd‐spenders‐2022/ 13 Discovery of Drug Candidates  Traditionally, drug discovery centred on substances derived from animal or plant sources (i.e., on natural products)  More recently (20th century), sources of natural origin include bacteria and fungi (e.g., penicillin)  Another source of drug leads include endogenous compounds  Screening programs 14 7 2024‐01‐08 Discovery of Drug Candidates – Natural Products in Target Identification  Many natural products are highly potent and selective towards (drug) targets due to their toxicity  e.g., snake venom, clostridial toxins, penicillins  Many natural products have been used to identify and characterize receptors:  Morphine (opiate receptors)  Strychnine (glycine (neuro)receptor antagonist)  Nicotine, muscarine (nicotinic and muscarinic acetylcholine receptors) 15 Discovery of Drug Candidates – Natural Products as Leads  Many biologically active natural products are rather poor in terms of therapeutic potential (toxicity, selectivity, addictive properties, etc.)  Morphine (although still used today) has been partly replaced by other opioids which are more potent, have a higher degree of selectivity (towards certain types of opioid receptors) or are less addictive  THC (Cannabis sativa) has been used to identify two cannabinoid receptors (CB1 and CB2)  Synthetic cannabinoid receptor ligands such as CP55,940 have been explored for the treatment of pain very lipophilic much less lipophilic (Pfizer) 16 8 2024‐01‐08 Discovery of Drug Candidates – Natural Products as Leads (2)  Teprotide (from the Brazilian pit viper) is a potent inhibitor of angiotensin‐converting enzyme (ACE) involved in blood pressure regulation  However, the viper toxin cannot be used therapeutically to lower blood pressure (cost, lack of oral activity)  Drawing inspiration from the structure of teprotide, N‐succinylproline was synthesized and found to inhibit ACE  Subsequent discovery efforts led to captopril (an analog of N‐succinylproline), which is much more potent and is one of the most commonly prescribed antihypertensive drugs 17 Lead development and optimization  In addition to being pharmacologically active, compounds must fulfill a number of other requirements including ADME of ADME‐Tox  Some of the issues:  Following oral administration, a drug must survive the harsh (acidic) environment of the stomach  A drug must survive exposure to digestive enzymes (a problem for peptidic drugs)  A drug should be unionized or slightly ionized to penetrate cell membranes to enter the blood stream (unless the drug can exploit other uptake systems such as transporters)  A drug should be somewhat resistant to the action of liver enzymes (involved in oxidation, reduction, hydrolysis, sulfation, … reactions) ADME = Absorption, distribution, metabolism, excretion 18 9 2024‐01‐08 Lead development and optimization Two useful definitions:  Pharmacokinetics → influence of the body on a drug as a function of time  deals with a drug’s rate of absorption/excretion, distribution in the body, and metabolic transformation  Pharmacodynamics → influence of the drug on the body as a function of time  deals with the drug’s interaction with the target(s), and its consequences Both pharmacokinetics and pharmacodynamics are related to a drug’s chemical structure! 19 In vitro, ADME profiles are used to identify compounds with drug‐like properties. They rely on a multitude of assays testing the following aspects: BBB: blood‐brain barrier Cyp450: Cytochrome P450s Pgp: P glycoprotein 20 10 2024‐01‐08 Important drug/lead characteristics Apart from ADME, the following characteristics must/should be satisfactory*  Freedom from mutagenesis and teratogenicity  Chemical (shelf) stability  Solubility * Medicinal chemists often modify or optimize lead compounds to achieve this, by: o Variation of substituents (size, shape, polarity)  Synthetic or biological accessibility; acceptable cost  Ability to patent o Extension/contraction of structure o Ring closures/variations/fusions  Clinical efficacy o Simplification of structure  Satisfactory taste (for oral drugs) o Rigidification of structure  Ability to formulate for administration 21 Lead development and optimization o Variation of substituents (size, shape, polarity) o Extension/contraction of structure o Ring closures/variations/fusions o Simplification of structure o Rigidification of structure 22 11 2024‐01‐08 Bioisosteres  Bioisosteres = molecules in which atoms/functional groups are modified (to generate new molecules with higher therapeutic potential)*  Bioisosteric replacement (“molecular mimicry”) is the most common method for the optimization of drug leads  Bioisosteric replacement can affect many molecular properties:  e.g., size, shape, electron distribution, solubility, pKa value, reactivity  As such, bioisosteric replacement can change the pharmacokinetic and ‐dynamic properties of a drug candidate  e.g., selectivity, potency, reduction of toxicity, metabolism, bioavailability * Example: ‐H can be replaced by ‐F, ‐Cl, ‐Br, ‐I, ‐OH, ‐CH3, NH2 23 Bioisosteres  Classical bioisosteres: Bioisosteres based on the observation that different atoms or functional groups with the same valence have similar biological properties ‐H to ‐F replacement often hinders metabolic oxidation (leads to longer half‐life) Procaine/novocaine (local anesthetic) Ring equivalents Procainamide* Na+ channel blocker *Procainamide has a prolonged duration of action compared to procaine 24 12 2024‐01‐08 Bioisosteres Grimm’s hydride replacement law  Other classical bioisosteres: 25 Bioisosteres  Nonclassical bioisosteres: bioisosteres where the replacements are not classical (they usually do not have the same geometric properties/size as classical ones) 1 1 tetrazole (metabolically more stable than COOH → liver metabolism) 26 13 2024‐01‐08 Bioisosteres  Examples of nonclassical bioisosteres: Xanthine is a natural substrate for xanthine oxidase (XO), an enzyme that produces uric acid and H2O2. Xanthine Oxypurinol (alloxanthine) → nonclassical bioisostere of xanthine Oxypurinol is a potent inhibitor of XO and is used in the treatment of gout. Arecoline is an agonist of the muscarinic acetylcholine receptor (so are its bioisosteres). Arecoline Bioisosteres of arecoline 27 Consideration of stereochemistry  Most drug targets are made up of chiral building blocks  Most drug‐binding sites (e.g., the active site of an enzyme) are therefore (essentially) chiral  The stereochemistry of the drug molecule is often critical to the pharmacological effects Eutomer = stereoisomer with the desired effect Distomer = stereoisomer that can be inactive, less active or detrimental 28 14 2024‐01‐08 Consideration of stereochemistry One of the early examples of how important it is to produce pure enantiomers is thalidomide (Contergan)  The racemic compound was introduced in 1957 as a sedative or non-addictive alternative to barbiturates  It was also discovered that thalidomide could be used to treat “morning sickness” in the early stages of pregnancy  In the early 1960s, the compound was linked to increasing numbers of severe birth defects in the offspring 29 15