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Matz's rule regarding medications: A drug is a substance which, when injected into a rat, will produce a scientific report.

Drug discovery, stock trading, and weather forecast are three things that are similar to me. They all have a distinguished feature called unpredictable. One of my friends asked me "how could you still keep your job so many years without discovering any drug?". It is a best question I ever heard for many years. Every medicinal chemist should stop feeling and start thinking! Prepared mind is better than experience, and experience is better than degree!

The Rule of Thumb in Medicinal Chemistry:

Rules of Pharmacokinetics: Some rules that could help you to improve a compound's pharmacokinetic properties, not activity or toxicity profiles.

Rules of five (Lipinski rule): (Pfizer)

1. Not more than five hydrogen bond donors, (OH, NH).
2. Molecular weight of a drug like molecule should be less than 500.
3. The logP of a drug like molecule should be less than 5
4. Less than 10 hydrogen-bond acceptors should exist in a drug like molecule, (O, N).
Rule of seven rotatable bonds: The bioavailability of a drug like molecule is related with it rotatable bond number. Less than seven rotatable bonds are essential for good bioavailablity. (GSK)
CNS drug rules: Compared with non CNS drugs, CNS drugs should have "fewer hydrogen bond donors, fewer positive charges, greater lipophilicity, lower polar surface area and reduced flexibility".-J. W. Polli (GSK)

Rules of Activity:

The size and shape of drug like molecule. The size and shape of a molecule are most important factors of its activity. Without certain size and shape, it is very difficult to talk about binding. The size and shape are more important than the interaction forces between small molecule and enzymes, receptors, and DNA or RNA. Without binding, there is no activity for sure.
Agonists vs. Antagonists. Generally speaking, agonists are much smaller in size and have less variations than antagonists, and much similar to natural ligands. On the another hand, antagonists could be bigger, many type of them, and far less similar with natural ligands.
Potency vs. in vivo efficacy.

Rules of Toxicity:

Toxicity first rule.
Drugs should not be extremely efficacious to cause some toxicity problem.

Fluorine in Medicinal Chemistry

Orthogonal Reactivity of Hydrogen and Fluorine.

Electronic effect: H⁺ vs F⁺. H⁺ is a frequent occurrence in reaction mechanisms; however, F⁺ is not capable existence (e.g. 5-FU).
Electronic effect: H^- vs F^-. Loss of H^- is a very energetic process, but F^- is a good leaving group (e.g. Eflornithine).

Effects of Fluorine Substitution on Adjacent Functional Groups.

Increase Hydrolytic Stability of Acid-Labile Groups because the inductive effect of a beta-fluorine greatly destabilizes a developing positive charge (e.g. TXA₂).
Enhance Electrophilicity in Enzyme Inhibitors.

CFH and CF2 are good replacements for O.

Fluorine Substitution is used in blocking metabolic pathway.

Fluorine Substitution may have positive conformation impact by having intramolecular hydrogen bonds.

Fluorine Substitution may have intermolecular effect by hydrogen bonds formation.

Reactions Related to Drug Metabolism

Drug Oxidation Pathway.

Drug Reduction Pathway

Acronyms and Abbreviations in Medicinal Chemistry

ACP acyl carrier protein

ADP adenosine diphosphate

AMP adenosine monophosphate

cAMP cyclic AMP

ATP adenosine triphosphate

ATPase adenosine triphosphatase

AUC area under curve, PK term

BMI body mass index

BPH benign prostatic hyperplasia

Cmax

CL total clearance

CL_Rrenal clearance

CML chronic myeloid leukemia

CNS central nervous system

CoA coenzyme A

CoQ coenzyme Q

COX-2 cyclooxygenase II

CSF cerebal synovial fluid

CYP cytochrome

DALYS disability adjusted life years

DNA deoxyribonucleic acid

cDNA complementary DNA

DNase deoxyribonulease

ECG ecocardiograms

ED erectile dysfunction

EGF epidermal growth factor

EPS extrapyramidal side-effects

F% bioavailibility

GI gastrointestinal

GISA glycopeptide-intermediate S. aureus

cGMP cyclic guanosine monophosphate

GPCR G-protein-coupled receptor

GTP guanosine triphosphate

Hb hemoglobin

HDL high-density lipoprotein

His histidine

HPL human pancreatic lipase

5-HT 5-hydroxytryptamine (scrotonin)

IgG immunoglobulin G

IP3 inositol triphosphate

ITP inosine triphosphate

LDL low-density lipoprotein

MDD major depressive disorder

MIC minimal inhibition concentration

MOA mechanism of action

NAD nicotinamide adenine dinucleotide

NADP nicotinamide adenine dinucleotide phosphate

NSAIDs non-steroidal anti-inflammatory drugs

OA osteoarthritis

PDGFR platelet-derived growth factor receptor

PG prostaglandin

PK pharmacokinetics

PLE pig liver esterase

PPH primary pulmonary hypertension

PPI proton pump inhibitor

RA rheumatoid arthritis

RNA ribonucleic acid

SAR structure-Activity relationship

SDAs serotonin-dopamine antagonists

SNRI serotoninand noradrenaline reuptake inhibition

T_1/2

TKI tyrosine kinase inhibitor

Vss steady-state volume of distribution

VLDL very low density lipoprotein

Terminology in Medicinal Chemistry

International Classification of Diseases

Infectious and Parasitic Diseases; Neoplasms (cancers); Endocrine, nutritional and metabolic diseases, and immunity disorders; Dieases of blood aand blood-forming organs; Mental disorders; Diseases of the nervous system and sense organs; Diseases of circulatory system; Diseases of respiratory system; Diseases of digestive system; Diseases of the genito-urinary system; Complications of pregnancy, childbirth and puerperium; Diseases of the skin and subcutaneous tissue; Diseases of musculoskeletal system and connective tissue; Congential anomalies; Conditions originating in the prenatal period; Symptoms, signs, and ill-defined conditions; injury and poisoning.

1. PK ( pharmacokinetics) Terms

ADME: Absorption, distribution, metabolism and excretion. For more check here.

Bioavailability (%F) is the metabolic availability of a drug or other chemicals to the target tissue after it has been introduced into a person's body. By definition, when a medication is administered intravenously (IV), its bioavailability is 100%. However, when a medication is administered via other routes (such as oral), its bioavailability decreases (due to incomplete absorption, first-pass metabolism, or fast elimination). Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration.

Clearance (CL) is the volume of blood/plasma from which all drug is removed per unit time. IV dosing is needed for calculating of total body clearance. The major drug elimination organs are kidney and liver. The drug metabolism related reactions include oxidation, reduction, hydrolysis and conjugation with polar molecules. Overall, clearance is affected by changes in perfusion (blood flow), permeability, transporters, intrinsic clearance and binding (plasma protein, blood, and tissues).

CL = Elimination rate/concentration (volume/time, L/hr or L/hr/kg)

Exposure (AUC and Cmax) IV and Oral. AUC is the area under plasma concentration time profile, it is depends on clearance, volume and dose. AUC = Dose/Cl; Cmax = Dose/Vdss. Drug exposure is important for prediction of human efficacious dose and multiples for toxicology coverage.

t1/2 and Mean Residence Time (MRT). t1/2 (half-life) is the time for the plasma (blood) concentration to fall by one half. It is depends upon clearance and volume of distribution. Mean Residence Time is the average time that all the drug molecules reside in body.

Pharmacodynamics (PD) is the study of the biochemical and physiological effects of drugs and mechanisms of drug action and the relationship between drug concentration and effect.

2. Clinic trial terms

IND: Investigation of new drug application

Preclinical:

Phase I: Phase I includes the initial introduction of an investigational new drug into humans. Phase I studies are typically closely monitored and may be conducted in patients or normal volunteer subjects. These studies are designed to determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. During Phase I, sufficient information about the drug's pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid, Phase II studies. The total number of subjects and patients included in Phase I studies varies with the drug, but is generally in the range of 20 to 80.

Phase II: Phase II includes the controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks associated with the drug. Phase II studies are typically well controlled, closely monitored, and conducted in a relatively small number of patients, usually involving no more than several hundred subjects

Phase III: A phase III trial frequently compares a new treatment to a standard treatment or to no treatment, and treatment allocation may be randomly assigned and the data masked. These studies usually involve a large number of participants followed for longer periods of treatment exposure. Phase III studies are expanded controlled and uncontrolled trials. Phase III studies usually include from several hundred to several thousand subjects.

NDA: New Drug Application. NDA refers to the data that the drug company submits to the FDA at the time of the drug's application filing.

Approvable: Term giving to a drug's approval status by the FDA. Before the drug can be launched, the company has to fulfill ongoing clinical and manufacturing concerns brought up by the FDA.

3. Drug Administation

Orally: The drug is administrated by month, it is the most common and desirable method of administration.

Sublingually: The drug is placed under the tongue.

Rectally: The drug is administrated by colon in the form of a solid suppository or in solution as an enema.

Intravenous (i.v.) injection: The drug is introduced directly into the circulation system.

Intramuscular (i.m.) injection: The drug is injected through the muscle.

Subcutaneous (s.c.) injection: The drug is delivered through the loose connective tissue of the subcutaneous layer of the skin.

Pulmonary absorption: The drug is administrated through respiratory tract in the form of gas or aerosol.

4. Drug Metabolism Terms

Drug Metabolism: The Process of enzymatic biotransformations of drugs in livers, kidney, lungs, and gastrointestinal (GI) tract into polar polar and non-toxic molecules which are excreted by the normal bodily processes is drug metabolism.

First-Pass effect: The drug metabolism by liver enzymes is called first-pass effect when a drug is carried via the bloodstream to live, where it is usually first metabolized.

Phase I Transformations: Reactions introduce or unmask functional groups, such as oxidation, reduction hydrolysis and demethylation.

Phase II transformations: Reactions generate highly polar derivatives by connecting with sugar (glucuronidation), sulfate (sulfate conjugation), and amino acid (amino acid conjugation) etc.

Hard Drug: Drugs are nonometabolizable compounds.

Soft Drug: Biologically active drugs have a predictable and controllable metabolic pathway to nontoxic substances after they have achieved their desired pharmacological effects.

5. Drug Effect Terms

Agonist: Chemical compounds that could cause the biological effects induced by the endogenous ligands are called agonists.

Antagonist: Chemical compounds that cause the biological effects by inhibiting the action of the endogenous ligands or agonists.

Inverse Agonist: Compounds inducing opposite biological effects to those induced by agonists are termed inverse agonists.

Drug Synergistic Action: One drug's biological effects increase by administration of another drug.

ED₅₀: The dose required to produce a specified intensity of effect in 50%.

LD₅₀: The dose required to cause 50% of individuals death.

TI: Therapeutic Index, is the ratio of LD₅₀ to ED_50.

Common Medical Expressions

Acute: A disease or illness that has a short duration but whose symptoms appear quickly and are severe.

Atrophy: The decrease in tissue size. Hypertropy: An increase of cell size. Hyperplasia: An increase in the number of cells.

Clinical: A term used to describe what is observable, capable of being examined, and treatable.

Chronic: A disease or illness that has a long duration with milder symptoms.

Complication: A secondary diease or disorder following the first condition.

Congenital: A condition present at birth. Congenital Anomaly: A birth defect.

Degeneration: The deterioration of cells or tissues. Regeneration: The repair of the original cells or tissues. Replacement: The growth of new cells or tissues.

Diagnosis: The determination of disease or disorder based on examining a patients.

Disease: A disorder of the body (or mind) in which body structures and functions are affected. Pathology is the study of diseases. Physiology is the study of the normal functioning of cells, tissues, organs, and systems. Etiology is the examination of the a disease.

Edema: The swelling of body tissue caused by an accumulation of fluid.

Enlargement: The abnormal increase in the size of an organ.

Genetic: Any condition developing from or caused by normal or abnormal genes.

Infection: The invasion of the body or part of the body by disease-causing microorganism.

Inflammation: The reaction of body tissues to injury.

Occlusion: The blocking of a passageway.

Prognosis: The determination of the course and the outcome of a disease and the patient's chance for recovery.

Symptoms: The signs of a disease.

Syndrome: A group of signs and symptoms that occur in specific pattern and indicate a particular disease.

Treatment : The application of some form of therapy either cure the disease or relieve its symptoms.

Trauma: A wound to tissue caused by an external agent.

Vital Signs: The indications of those processes necessary to sustain the life of an organism.