Methods In Drug Discovery Part 1

Define the term "drug discovery" - A compound is found which is biologically active in the desired therapeutic area Define the term "drug development" - A compound discovered to be biologically active then has that activity and its toxicology optimised for the clinic - Until an active and toxicologically safe When is the process of obtaining a new compound is identified and fully biologidrug finished cally tested Briefly describe the pathway of drug discovery leading to development What is angiotensin II - Is an octapeptide and is a potent vasoconstrictor which increases blood pressure How is angiotensin II produced? - It is produced from angiotensinogen and angiotensin converting enzyme (ACE) What occurs in the inhibition of ACE - Inhibition of ACE will prevent the raising of blood pressure - Captopril - Belongs to a class of drugs as anName a drug that primarily treats high giotensin-converting enzyme (ACE) inblood pressure (hypertension) and heart hibitors failure - Captopril inhibits the action of ACE, which is responsible for converting angiotensin I to II - Drugs structurally like existing medications, often belonging to the same class - Exert similar pharmacological effects What is meant by a "me too" compound but may have slight differences in structure, formulation or pharmacokinetics - Developed to capitalize on the success of existing drugs and offer therapeutic 1/5 alternatives - Definition: a "me too" drug is a drug containing an API which is chemically related and very structurally like an existing API - Captopril is often regarded as a groundbreaking medication that marked the beginning of a new class of drugs known as ACE inhibitors - Series of derivatives were made based on the rationally designed drug, anDescribe the significance between capgiotensin converting enzyme (ACE) intopril and "me too" compounds hibitors - Avoidance of patent issues - Improved efficacy i.e. better potency and specificity of action State the considerations when designing - Improved safety profile a "me too" compound - Allows for an improved formulation which is easier to administer - Improved physical properties which affect pharmacokinetic parameters How and why did the US Food and Drug - The patent was not good enough; even Administration (FDA) approved AmVaz the most subtle changes (i.e. the countethrees years before the patent for Norrion) should be covered vasc was due to expire What is cholinomimetic therapy - Use of drugs that mimic or enhance the effects of acetylcholine, a neurotransmitter - E.g. Selectivity between the 5 subtypes of muscarinic receptors M1-M5 2/5 - Involves targeting muscarinic receptors i.e. the receptor sites for the neurotransmitter, acetylcholine - Mainly located at the postsynaptic cell membranes of smooth muscle, cardiac Describe the therapy for Alzheimer's dismuscle and glandular tissue but occur ease throughout the body, particularly in the brain - When activated, the receptors release acetylcholinesterase (AChE) which breaks down acetylcholine What is the main therapeutic effect of cholinomimetic therapy in Alzheimer's disease - Increasing levels of acetylcholine Which brain regions are affected by the loss of neurons in Alzheimer's disease - Basal forebrain, cerebral cortex, and hippocampus What is the role of acetylcholine in choli- To bind to the M1 receptor and potennomimetic therapy for Alzheimer's distially compensate for lost neurons ease What are the subtypes of cholinomimetic receptors - M1-M5 Why are cholinomimetic receptors collectively known as muscarinic acetylcholine receptors - Due to their ability to bind muscarine - M1 and M2 Describe which cholinomimetic receptor - Similar secondary structures (7 transsubtypes are very similar membrane alpha-helices); similar tertiary structures - M1 is localised >90% in the CNS Describe the difference in distribution of - M2 is widely distributed in other tissues the M1 and M2 receptor subtypes as the heart and smooth muscle How was himbacine adapted - Known to bind to the M2 receptor - Was adapted to increase M1 specificity and therefore increase its potency 3/5 What is ribavirin - An antiviral agent used in the treatment of severe lower respiratory tract infections caused by respiratory syncytial virus (RSV) - Is a guanosine analogue Describe the action of ribavirin - The end-caps viral mRNA and stops viral RNA synthesis State and describe a drawback of ribavirin - Hemolytic anemia is a side effect owing to the phosphorylation of this compound - This leads to mono and tri-phosphorylated metabolites which affect the red blood cells - Has been shown to be safer in a number Describe the significance of the opposite of animal studies enantiomer of ribavirin - Does not phosphorylate, therefore no hemolytic anemia - Each of a pair of molecules that are mirror images of each other - Non-superimposable mirror images of each other; like your hands What is an enantiomer - Loratadine (antihistamine) which can What is an example of improved formube taken orally instead of through injeclation in medication? tion - A promising research compound was predicted to last only 6-8 hours in huHow was the half-life of a research commans pound extended to allow for oral intake - By adding a chlorine atom to the compound What is a major metabolic pathway of the - Hydroxylation at the para position of the antihistamine tripelennamine benzene ring How can the metabolic pathway of tripelennamine be blocked - By halogenation What are the effects of blocking the metabolic pathway of tripelennamine - Longer half-life and improved drug activity 4/5 - High probability of ending up with an active molecule - If enough copies are then there is a good chance of finding a compound with an improvement on the efficacy of the original (i.e. better potency and specificity of action) State and describe the pros of "me too" - Show a different profile of adverse efcompounds fects (i.e. improved safety profile) - Previous information is available - Can work in patients who do not respond to the original drug - Can be less expensive than the original or drive down prices - Occasionally, very different properties can be discovered - Not very innovative - Can be seen as simply a way of propping up the pharmaceutical industry with minimal effort (and minimal clinical adState and describe the cons of "me too" vantage) compounds - 3 patents are often difficult to get around and the original inventor will already have covered most variations - Unlikely to lead to dramatic or radical improvement over existing treatments 5/5