Drug Design Lecture 1 PDF

## Optimizing Pharmacokinetic Properties - A lot of problems in **Metabolic Stability** and **Absorption** are encountered in **Pharmacokinetic**. ### Improving Absorption: - **Log P, pKa** are the main factors controlling the *Absorption* in Physicochemical properties. - If **Log** is too high o...

## Optimizing Pharmacokinetic Properties - A lot of problems in **Metabolic Stability** and **Absorption** are encountered in **Pharmacokinetic**. ### Improving Absorption: - **Log P, pKa** are the main factors controlling the *Absorption* in Physicochemical properties. - If **Log** is too high or too low, the absorption will be low. #### Examples: | Example | Description | | -------------------------------------------------------------------------- | ------------------------------------------------------------------------------------------------- | | **Acyclovir** | *Low polarity, high absorption (<85-90%)* | | **Valacyclovir (Prodrug)** | *Masking the hydroxyl group with a methyl group to make it less polar, resulting in high absorption (~90%).* | | *Frequency of dose: 6-8 Times daily. Med. use: Antiviral in Herpes infection.* | *Withdrawal: Poor absorption because of high polarity. Absorbed by 15% only.* | | *Optimized absorption: Varied alkyl substitution in drug latentiation.* | | ## Improving metabolism: ### Techniques: #### 1. Steric Shields - This technique is used to protect esters or amides from undergoing Hydrolysis by esterase or amidase enzymes. - Steric shields can be used to block these enzymes from accessing the ester or amide group. - Example: **Bulk tert-butyl group** (protects Amide from amidase). - **Antiarrhythmic drug**, called: **steric shield**, results in 50% metabolic stability. #### 2. Acetyl Choline (important example) - Acetyl Choline has two issues: **dynamic** and **kinetic**. - Solution: **Steric shields** | Example | Description | | -------------- | ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | | **Methacholine** | *Metabolite stable & also selective at muscarinic receptor. It prevents hydrolysis by esterase enzyme. Steric shield (CH3) and electronic effects are used to protect this drug from destruction by esterase enzyme.* | #### 3. Stereoelectronic Modification (Steric shield + Electronic effect) | Example | Description | | --------------- | ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- | | **Acetylcholine** | +CH3 group is added to make it **Bethanechol** this creates a steric shield to prevent hydrolysis. CH3NH2 is also added to provide an electron-donating group, also contributing to increased stability. | | **Lido Procaine** | *This drug is an ester. Its electrophilicity is lower than that of **Lidocaine** (an amide) due to the electronic effect. Steric hindrance with two methyl groups are used to prevent the degradation of the ester via **procaine**.* | #### 4. Metabolic Blockers - Progesterone, which has a hydrogen on a specific carbon, is vulnerable to metabolism. - The solution is to replace that hydrogen with **OCOCH3**. - This results in **Megesterol acetate** which demonstrates increased metabolic stability.