Lectures 17_Physicochemical properties of Drug molecules-2_Henderson HasselBach Equation; Chiral Drugs PDF

Medicinal Chemistry Drug Physicochemical Properties of Drugs - 1 Functional Group (FG) 1. Electronic Effects, 2. Steric Effects, 3. Acidity and Basicity of FG Physicochemical Properties of Drugs- 2, 3 4. Chirality...

Medicinal Chemistry Drug Physicochemical Properties of Drugs - 1 Functional Group (FG) 1. Electronic Effects, 2. Steric Effects, 3. Acidity and Basicity of FG Physicochemical Properties of Drugs- 2, 3 4. Chirality 5. Salt and Solubility  Physicochemical properties of Drug molecules -1 Chemical Properties of Functional FG Groups FG is a part of a compound/drug which provides specific properties and behaviors that allow a compound/drug to produce biological response. Chemical Properties of FGs: (1) Electronic Effects: Resonance and Inductive Effect (2) Steric Effects (3) Acid-base Properties (4) Chirality (5) Solubility Effects: Water and Lipid Solubility, Salt Formation Lecture # 17  Henderson-Hasselbach FG 3. Acid-Base properties Equation First described by Lawrence Henderson in 1908 and later revised by Karl Weak Acids Hasselbach in 1916. HA H + A Acid Conjugate Base [ionized] [un-ionized] [acid] or pKa = pH + log [conjugate base]  Weak Bases B:H H + B: Conjugated Acid Base (Protonated (Unprotonated Form) Form) [base] pH = pKa + log [conjugate acid] [un-ionized] or pH = pKa + log [ionized]  FG Addition properties Calculation of percent ionization of amobarbital at pH 2.0, pH 8.0, and pH 7.4. Foye's Principles of Medicinal Chemistry At a pH of 8.0 there are equal amounts of acid form and conjugate base (or ionized) form: - [A ] 8 = 8 + log [HA] - [A ] 0 = log [HA] - 0 1 [A ] 10 = = 1 [HA] [A-] + [HA] = 1 + 1 = 2 - [A-] % [A ] = - X 100 [A ] + [HA] 1 - % [A ] = X 100 = 50% 2  FG Addition properties pH = 7.4 - [A ] 7.4 = 8.0 + log [HA] - [A ] -0.6 = log [HA] 0.25 [A-] = 1 [HA] [A-] + [HA] = 1 + 0.25 = 1.25 - [A-] % [A ] = X 100 [A-] + [HA] 0.25 X 100 = 20% % [A-] = 1.25 The calculation indicates that 20% of the molecules are in the conjugate base (or ionized) form, leaving 80% in the acid (unionized) form. Foye's Principles of Medicinal Chemistry  At a pH of 5.5, the acid form predominates (99.7%). At pH 2.0 amobarbital is in the acid or unionized form (100%) since the pH is 6 log units below the pKa of the compound.  FG 3. Acid-Base properties Calculation of percent ionization of phenylpropanolamine at pH of 2.0 and pH of 5.5. Foye's Principles of Medicinal Chemistry  2.0 = 9.4 + Log [un-ionized]/[ionized] Unionized is the base form and ionized is the conjugate acid. 2.4 – 9.4 = Log [un-ionized]/[ionized] -7 = Log [un-ionized]/[ionized] or 7 = Log [ionized]/[un-ionized] [un-ionized]/[ionized] = 10-7/1 or [ionized]/[un-ionized] = 107 Percentage of ionization = 107/(1 + 107) X 100 = 99.99% At a pH of 2.0 the compound exists in the conjugate acid (ionized) form (>99%) as shown. At a pH of 5.5 phenylpropanolamine is 99.7% ionized, and at pH 8.0 the conjugate acid form still predominates, but it has decreased to 96%.  Pharmacist Trapping of Morphine in Alert Stomach The drug is slightly more than 50% nonionized in the plasma (pH approximately 7.4) because it is in an environment with a pH that is slightly less than pKa. In the stomach (pH approximately 2), the drug is highly ionized, it cannot diffuse across the cells lining the stomach, and the drug molecules are trapped in the stomach. https://clinicalgate.com/pharmacokinetics/ Pharmacist Alkalinization of Urine Alert to Eliminate Drugs Alkalinization of the urine is used to increase the excretion of acetylsalicylic acid (aspirin), an acidic drug. Increasing the pH of urine above the pKa of acetylsalicylic acid increases the proportion of the drug in the ionized state by about 10,000 times. https://clinicalgate.com/pharmacokinetics/ Pharmacist Alert Urine Alkalinization Urine alkalinization is a treatment regimen that increases poison elimination by the administration of intravenous sodium bicarbonate or oral tablets to produce urine with a pH > 7.5 or more. Urine alkalinization increases the urine elimination of mecoprop (herbicide), methotrexate, phenobarbital, and salicylate. Mecoprop Methotrexate Phenobarbital Pharmacist AlertAcid, Base, and Absorption Ecstasy gets into the brain easily. Ecstasy is a weak base. Once the Ecstasy has accepted a H+, it has a charged character, which makes it difficult to cross a biological membrane. Therefore, most of the Ecstasy is not absorbed from the stomach into the bloodstream. In the small intestine the more alkaline environment causes Ecstasy to give up its H+, becoming nonpolar, enabling the Ecstasy molecules to diffuse across the membrane into the blood capillaries. Eventually Ecstasy crosses the blood brain barrier into the brain very easily. It will take about 15 min. for Ecstasy to reach the brain if taken on empty http://www.nida.nih.gov/teaching4/teaching2.html stomach.  Rule of thumb Weak acids— HA ↔ A- (—COOH ↔ —COO–) – When pH is below the pKa, acids are more likely to be in the un-ionized (HA) form. The un-ionized form can diffuse through lipid membrane. Weak bases— BH+ ↔ B (—NH3+ ↔ —NH2) – When pH is below the pKa, bases are more likely to be in the ionized (BH+) form. The ionized form will not diffuse through lipid. In the stomach (at pH 2), most acids will diffuse through membrane (absorb), but bases will not. In the small intestine (at pH 4.8-8.2), most acids will not absorb, but most bases will.  Key Facts to Remember! How to use the Henderson-Hasselbach Equation for calculating the percentage of ionization Calculate % ionization in the given drug at the provided pH. For acidic drugs when pH > pKa, mostly ionized. For acidic drugs when pH  pKa, mostly unionized. For basic drugs when pH > pKa, mostly unionized. For basic drugs when pH  pKa, mostly ionized.  Physicochemical properties of Drug molecules -1 Chemical Properties of Functional FG Groups FG is a part of a compound/drug which provides specific properties and behaviors that allow a compound/drug to produce biological response. Chemical Properties of FGs: (1) Electronic Effects: Resonance and Inductive Effect (2) Steric Effects (3) Acid-base Properties (4) Chirality (5) Solubility Effects: Water and Lipid Solubility, Salt Formation  3. Chirality Stereochemistry (The orientation of functional groups in three-dimensional space is referred to as the molecules’ stereochemistry.) Asymmetric Carbon (chiral carbon): A carbon atom attached to four substituents that are different. Amoxicillin A molecule containing “n” asymmetric carbons will give rise to 2n optical isomers. The spatial arrangement affects the way it reacts in chemical reactions and its biological and physical properties Molecules with the same molecular formula but differing in the arrangement of their atoms in space are called stereoisomers. Stereoisomers may have very different biological properties. For example, Ibuprofen exists as a racemic mixture, but only the S enantiomer has analgesic properties.  Different types of stereoisomers: enantiomers, diastereomers, geometric Enantiomers: non-superimposable mirror image isomers Diastereomers: non-superimposable, non- mirror image. isomer (more than one chiral center) Geometric isomers (diastereomers): E / Z alkene isomers  Absolute configuration (Cahn-Ingold- Prelog rules) The description of the order of the ligand atoms in space (Spatial H 1 Arrangement) C 6 N 7 R, S convention is determined by the O 8 atomic numbers of the F 9 P 15 substituents closest to the S 16 stereogenic center. Cl 17 R (rectus, “right”: “clockwise”) Br I 35 53 S (sinister, “left”: “counter-clockwise”) The Absolute Configuration (the precise three-dimensional arrangement of atoms in space) can be assigned by the R/S method as follows: (1) Assign priorities to the ligands from 1 (highest priority) to 4 (lowest priority). (A substituent with a higher atomic number takes precedence over a substituent with a lower atomic number. Hydrogen is the lowest possible priority substituent because it has the lowest atomic number.) (2) Rotate the molecule so that ligand number 4 is in the back. (Dashes indicate pointing away from the viewer.) (Wedges indicate coming towards the viewer.) (3) If the direction for the numbers 1 to 3 is clockwise, assign R (rectus, Right), if counterclockwise, assign S (sinister, LEFT). H N (R) H H2N (S) Problems: Solutions: 1. S: I > Br > F > H. The lowest priority substituent, H, is already going towards the back. It turns left going from I to Br to F, so it's a S. 2. R: Br > Cl > CH3 > H. You have to switch the H and Br in order to place the H, the lowest priority, in the back. Then, going from Br to Cl, CH3 is turning to the right, giving you a R. 3. Neither R or S: This molecule is achiral. Only chiral molecules can be named R or S. 4. R: OH > CN > CH2NH2 > H. The H, the lowest priority, has to be switched to the back. Then, going from OH to CN to CH2NH2, you are turning right, giving you a S. (5) S: −COOH > −CH2OH > C≡CH > H. The H, the lowest priority, has to be switched to the back. Then, going from −COOH to −CH2OH to −C≡CH you are turning left, giving you an S configuration  Stereochemistry and Biologic Activity Easson-Stedman Hypothesis They postulated that such interactions require a minimum of a three-point fit to the receptor (minimum of three intermolecular interactions) The less potent enantiomer interacts with less sites.  Drug receptor interaction of R-(−)-epinephrine, S-(+)- epinephrine, and N-methyldopamine Optical isomers. Only in compound 6 do the functional groups A, B, and C align with the corresponding sites of binding (A′, B′, and C′) on the asymmetric surface.  Optical Rotation []D of plane Polarized light. (+) = d (dextrorotatory) (-) = l (levorotatory) Note that the sign of optical rotation (+) or (-) is not related to the R, S designation (+) and (-) refer to the effect of the compound on the direction of rotation of plane- polarized light and have nothing to do with the stereochemical configuration of the molecule.  Key Points Enantiomeric: Not Superimposable Racemate: An equal mixture of two enantiomers Amino acids are chiral molecules (All L- isomers) Proteins are also chiral. The interactions between chiral proteins (receptors) and different enantiomers of chiral drugs may involve different binding sites. Different Scenarios (Interesting facts) A. One enantiomer is more potent than the other – The S-(+)-isomer of antihistamine dexchlorpheniramine is 200 times more potent than the R-(-)-isomer. B. Both isomers are biologically active, but only one contributes to the toxicity – Fluoxetine  (±)Fluoxetine (Prozac), E. Lilly R and S isomers are equally potent as selective serotonin reuptake inhibitor (SSRI) R isomer shows small but significant cardiac side effect S isomer works well for the anti-migraine effect, but a racemic mixture has no effect. https://www.youtube.com/watch?v=cWx6RbBVTnA Pharmacist Alert C. One isomer may contribute to undesirable side effects and significant toxicity Currently used for – thalidomide advanced leprosy and multiple myeloma, and various other solid and hematologic malignancies. over 10,000 babies wer affected by the drug worldwide. Around half Birth defect was caused by the (S)-isomer died within months of (R)-Isomer was converted in to the (S)-isomer in vivoborn. being D. Enantiomers may have different therapeutic activities. Darvon, 2R, 3S-(+)-dextropropoxyphene, is an analgesic drug. Novrad, 2S,3R-(-)-levopropoxyphene, is an antitussive agent. E. It, also, is possible for enantiomers to have opposite effects. The (+)-isomer of the experimental narcotic analgesic picenadol is an opiate agonist, the (-)- isomer is a narcotic antagonist, and the racemate is a partial agonist. F. Two enantiomers may have synergistic pharmacological activities. The (+)-isomer of the antihypertensive drug nebivolol (Nebilet) is a -blocker. The (-)-isomer is not a -blocker, but it is still a vasodilating agent (via the nitric acid pathway). The drug is sold as a racemate to take advantage of two different antihypertensive  Separation of enantiomers In general, about a third of drugs are sold as racemic mixtures, even though at least half of the mixture not only may be inactive for desired biological activity, but may, in fact, be responsible for various side effects. It can be quite expensive to separate the enantiomeric impurity. The FDA has been satisfied if the racemate has low toxicity in human studies.  Chiral drugs and the market New patent for marketing single enantiomer even the racemate is covered by an active patent. AstraZeneca marketed the antiulcer drug omperazole (prilosec) as racemate. Shortly before the patent expired, a new patent was issued to the same company for the active (S)-isomer which was approved for marketing as esomeperazol (nexium). Single isomer drug sales have been steadily increasing worldwide.  Key Points Identify chiral carbon atoms that are present in the drug molecules. Be able to analyze drug structure to find the number of chiral carbons Analyze absolute configuration in a given drug molecule. Understand the differential potency and efficacy of stereoisomeric drug molecules.  Medicinal Chemistry Drug Physicochemical Properties of Drugs - 1 Functional Group (FG) 1. Electronic Effects, 2. Steric Effects, 3. Acidity and Basicity of FG Physicochemical Properties of Drugs- 2, 3 4. Chirality 5. Salt and Solubility