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14 Cards in this Set
- Front
- Back
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what factors make a good oral drug? |
- It must be soluble
• Be stable under a range of pH’s (1.5-8.0) • It must avoid excessive metabolism in the kidneys and liver • Be able to cross the cell membrane and reach its target organ • It must also avoid partitioning into undesirable places like the brain orthe foetus |
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what is H bond? how is it formed? |
A H-bond is a non-covalent interaction/bond which can form between a Hbonddonor and an acceptor. The donor is a H-atom attached to anelectronegative atom (e.g. N, O, F). The acceptor is a neighboringelectronegative atom which has a lone pair of electrons. A
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what is Lipinski's rule of 5? |
• MW < 500 Da
• LogP < 5 • H-bond donors < 5 • H-bond acceptor < 10 |
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what does lower pka value tell you as an acid? |
lower pka, stronger the acid |
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What does renin-angiotensin system regulate? |
- blood volume - arterial blood pressure - electrolyte balance |
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what are the physicochemical and pharmacokinetic properties of first ACE inhibitor? |
The first ACE inhibitor: Captopril - it is a potent inhibitor of ACE - SH group (thiol group) as Zn chelator; increased affinity and bioavailability over lead compounds - the carboxylic acid group of proline C terminal forms an electrostatic interaction with lysine residue in the enzyme active site - side effects; skin rashes and metallic taste disturbance due to thiol group - short duration of action due to the amine group (polar) |
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what is SAR? |
Structure activity relationships Adjusting the lead compounds into the improved potency and efficacy by modifying the structure of the compound |
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what is a transition state of enzyme-catalysed reaction? |
A transition state is a high-energyintermediate formed on the pathway from reactant/substrate to product.
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what was the lead compound of captopril inspired from? |
The lead compound was inspired by benzylsuccinic acid - an inhibitor ofa related enzyme Carboxypeptidase A and peptide inhibitors found insnake venom
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what is the drug class of 2nd generating ACE inhibitors? what was the major change? |
Dicarboxylate class changing the Zn chelator from thiol group (SH) into carboxylate group |
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what is chelator? |
a binding agent that suppresses the chemical activity |
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what are the examples of 2nd ACEIs? |
Enalaprilat (IV only) Enalapril (pro drug) Quinapril (pro drug) Ramipril (pro drug) Lisinopril |
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Prodrug strategy is not necessary for lisinopril. Why? |
Lisinopril is more polar than other compounds but in intestine 2 carboxylic acid groups and 2 primary amine groups are all charged, and there is no net charge |
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what are the key features of dicarboxylate class of ACE inhibitors? |
• The dicarboxylate class of inhibitors were designed to mimic the tetrahedralintermediate or the transition state of the enzyme catalyzed reaction. • The carboxylate chelates the zinc • The proline was found to be essential as before, with the carboxylate formingan electrostatic interaction with positively charged lysine residue in theenzyme active site • The phenyethyl functional group mimics the essential phenylalanine residue inangiotensin I – binds in a hydrophobic tunnel in the enzyme active site • With the exception of Lisinopril this class of inhibitors need to beadministered as prodrugs (highly charged at physiologically relevant pH) –here the carboxylate group is masked by converting it to an ethyl ester. Theactive drug is released in vivo: hydrolysis by esterase’s.
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