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Pharmacology 4001: Mechanisms of Drug Action Lecture 7: Drug Discovery and the Development of Novel Therapeutics Feb 6, 2024 Learning Objectives. List the key steps in the drug development process.. Name 5 sources of new drugs and an example drug in each category.. Describe the objective of Phase I...

Pharmacology 4001: Mechanisms of Drug Action Lecture 7: Drug Discovery and the Development of Novel Therapeutics Feb 6, 2024 Learning Objectives. List the key steps in the drug development process.. Name 5 sources of new drugs and an example drug in each category.. Describe the objective of Phase I vs. Phase II vs. Phase III clinical trials.. Describe the drug development process in terms of length, expense, and likelihood of success. Drug Use in Context Use of medicinal plants probably predates civilization. Even some animals appear to ‘selfmedicate’ (i.e., exploit plants for medicinal purposes.) Loading… https://www.pnas.org/doi/full/10.1073/pnas.1419966111 Chimpanzees in Tanzania eat aspella leaves whole, nearly exclusively when they have intestinal parasites. It is thought that they are using the leaves and stems to scour their intestines and rid themselves of parasites. 1. 2. 3. 4. 5. Sources of New Drugs Natural products Synthetic Chemicals Biotechnology Repurposing Structure-based in silico docking or screening Loading… Sources of New Drugs: Natural Products ~ 50% of current drugs are either natural products or derivatives of natural products Quinine (prevention and treatment of malaria, derived from the bark of a cinchona tree native to South America) Paclitaxel (anti-cancer, isolated from the bark of the Pacific yew trees) Cocaine (local anesthetic and vasoconstriction, derived from coca leaves grown in Bolivia, Peru, and Colombia) Reserpine (anti-hypertensive, derived from the roots of certain species of the tropical plant Rauwolfia) Aspirin (anti-inflammatory/analgesic, derived from salicylic acid found in the bark and leaves of the willow and poplar trees) Opium (analgesics, extracted from the poppy plant, Papaver somniferum) Snake venom peptides (ACE inhibitors, anti-hypertensives) Sources of New Drugs: Natural Products Many drugs were originally derived from microbial sources Antibiotics – penicillin, cephalosporins, tetracyclines, aminoglycosides, glycopeptides Anti-cancer – bleomycin, doxirubicin, mitomycin, captothecin Immunosuppressants – cyclosporin, tacrolimus Cholesterol-lowering agents – lovastatin 1. Sources of New Drugs: Synthetic Chemicals Synthetic dyes 2. – Dyes not developed for medicinal purposes originally, for garment industry – Later found to have anti-parasite activity – Example: ‘Trypan’ named for interaction with the parasite Trypanosoma brucei which cause African Trypanosomiasis (sleeping sickness) and Chagas disease Coal tar 3. – Acetaminophen (paracetamol) Large chemical libraries https://pubmed.ncbi.nlm.nih.gov/21080764/ https://www.smithsonianmag.com/smart-news/researchers-develop-eco-friendly-method-synthesizing-tylenol-plants-180972582/ Sources of New Drugs: Synthetic Chemicals Large synthetic chemical libraries (containing 500,000 – 3 million chemicals). Often biased to satisfy Lipinski’s “rule of five”, which is an approximation of whether the chemical has potential as an oral available drug. i) No more than 5 hydrogen bond donors ii) No more than 10 hydrogen bond acceptors iii) A molecular mass less than 500 daltons iv) An octanol: water partition coefficient (log P) that does not exceed 5 Note: LogP is a measure of lipophilicity. High lipophilicity (logP>5) can lead to high metabolic turnover, low solubility, and poor oral absorption. In addition, highly lipophilic compounds tend to bind to hydrophobic targets other than the desired target, and, therefore, there is an increased risk of promiscuity and toxicity. There are exceptions, but the rule is often used to assess absorption, distribution, metabolism and elimination properties. Sources of New Drugs: Synthetic Chemicals Maraviroc (Selzentry/Celsentri; Pfizer) is an example of the power of high-throughput screening (HTS) coupled with medicinal chemistry efforts to optimize pharmacological and pharmacokinetic properties. The program began with HTS of the Pfizer library (~500,000 compounds) in 1997 and ended with the US Food and Drug Administration (FDA) approval of Maraviroc in 2007. Maraviroc is a CCR5 antagonist that inhibits the entry of HIV into host cells. https://www.nature.com/articles/nrd3368 Sources of New Drugs: Biotechnology Loading… Johnson, I. (2003). Nature Rev. Drug Disc. 2: 747-751. Example: Human insulin for diabetes One of the first uses of recombinant DNA technology Controversial in the 1980s Originally done at biosafety levels III or IV Slowed down application of molecular biology to disease Sources of New Drugs: Repurposing/Repositioning Drug repurposing/repositioning: Identify new indications for already-approved or alreadyclinically tested drugs Drug repositioning plays a crucial role in drug development – Lowers the overall developmental costs by ~$300 million. – Results in lower development risk as the safety of the repositioned drugs has already been well established in humans and other preclinical models. – Involves a shorter development timeline, as there is no need to repeat the safety assessment and formulation development protocols since they are already in place. https://pubmed.ncbi.nlm.nih.gov/30310233/ Sources of New Drugs: Repurposing/Repositioning Note the importance of clinical observations and serendipity Examples: – Sulfonamides for many indications (bind multiple targets) – Viagra for erectile dysfunction (binds the same target, phosphodiesterase type-5 (PDE5), which can be useful in multiple instances) Sources of New Drugs: Structure-Based in silico Docking or Screening Instead of screening 1 million compounds in a pharmacological assay, in silico screening allows for the assessments of 1 billion compounds, virtually Examples of de novo in silico screen to an FDA approval… – Not that I know of – This is still relatively new – Hopefully examples are soon to come https://www.nature.com/articles/s41596-021-00597-z The Drug Development Process Pre-clinical Clinical 1. Preclinical Development (In Vitro and Animal Testing) Target Identification 1907: drugs proposed to function by acting through “chemical receptors” Identification of a protein or nucleic acid that is believed to have a role in the disease. In many cases the target does not correct the underlying disease but is able to compensate for it. Types of targeting being exploited pharmacologically 1. Preclinical Development (In Vitro and Animal Testing) Assay Development A rapid means to determine when the target is inhibited by a potential drug. Requires an assay in which the engagement of the target results in a change in color, florescence or some other readily measured property The assay is required to be high throughput so that upwards of a million different compounds can be rapidly tested 1. Preclinical Development (In Vitro and Animal Testing) Assay Development 96 Wells 384 Wells 1,536 Wells 1. Preclinical Development (In Vitro and Animal Testing) Identification of Lead Compounds Large libraries of chemicals that could be obtained from either natural or synthetic sources In silico screening 1. Preclinical Development (In Vitro and Animal Testing) Identification of Candidate Drugs Optimization of binding affinity and efficacy both in vitro assays and in animals SAR=structure-activity relationship studies Minimization of toxicity Optimization of solubility and bioavailability The Drug Development Process Pre-clinical Clinical Clinical Development FDA New Drug Approval Process (12 yr on average), high rate of failure, expensive. Phase 1 (20-100 healthy volunteers) – Purpose: mainly safety (several months) – Also involves dosage optimization, measurement of distribution, metabolism and elimination. Phase 2 (several hundred volunteer patients, with diagnosis according to targeted indication) – Purpose: safety, efficacy, dosing (several months). Phase 3 (several hundred to greater than 5,000 patients, with diagnosis according to targeted indication) – Purpose: safety and efficacy (1-4 years) Clinical Development Clinical Development: Success Rates Overall failure rate in drug development is >96%, including a 90% failure rate during clinical development. Failure rates are highest for drugs with a new mechanism of action against a previously ‘undrugged’ protein, and for diseases (e.g., Alzheimer’s disease) where the pathogenesis is poorly understood. https://www.nature.com/articles/s41598-019-54849-w Most drugs fail due to lack of efficacy Clinical Development: Success Rates Clinical Development: Costs The mean cost of developing a new drug is between $314 million to $2.8 billion, depending on how failed trials are accounted for. The median research and development cost of bringing a single cancer drug to market was $780 million in 2018 (in 2018 US dollars). Clinical Development For clinical trials of anti-cancer drugs, Phase I and II are usually combined. Why? The Drug Development Process: Post-Market Monitoring Pre-clinical Clinical Loading… Even when it’s over, it’s not over Bonus #1 Phase 1 trials have gone horribly wrong What could have caused this and why wasn’t the problem detected in the pre-clinical studies (5 bonus points)? Learning Objectives. List the key steps in the drug development process.. Name 5 sources of new drugs.. Describe the objective of Phase I vs. Phase II vs. Phase III clinical trials.. Describe the drug development process in terms of length, expense, and likelihood of success. Homework Assignments for Jan 16 – Feb. 13 Complete Quiz #6 by Thursday at 9:05 am. On Canvas. Two attempts. Download RESEARCH PAPER #1: Druker at al. (1996). Effects of a specific inhibitor of the Abl tyrosine kinase on growth of Bcr-Abl positive cells. Nature Medicine 2, 561-564. – Start reading and prepare to discuss during lecture on Feb. 13 (First student presentations will be on this day. Figure/Table assignments are available on Canvas.)