Chemistry of ACE inhibitors Flashcards
What is the function of ACE?
Whhat group of enzymes do ACE belong to?
What is the function of AII?
Converts angiotensin I to angiotensin II by removing the dipeptide His-Leu
Belongs to zinc metalloproteinases (membrane-bound enzyme)
Zinc ion = cofactor (important to binding + mechanism)
Angiotensin II constricts blood vessels + raises BP
ACE inhibitors used as antihypertensive agents
Draw the catalysis mechanism for coagulation protease thrombin
Function of the Zinc in Zn-containing proteases
Describe the development of ACE inhibitors
Problems in extracting ACE from blood - it’s membrane-bound
The approach in designing an ACE inhibitor was to inhibit an equivalent enzyme (similar active site + function to ACE) which can be isolated - e.g. carboxypeptidase
What is carboxypeptidase?
Carboxypeptidase is an enzyme that catalyzes the hydrolysis of proteins at their C-terminus
Inhibited by L-benzylsuccinic acid
‘zinc metalloproteinase’ - metalloenzyme containing Zn2+ at its active site
From researching carboxypeptidase + how L-benzylsuccinic acid inhibits it,how does this help develop an ACE inhibitor?
Carboxypeptidase cleaves off 1 amino acid; ACE cleaves off 2 - ACE active site must be bigger
That meant they used an analogous inhibitor which would be longer by 1 amino acid
Used a succinyl-substituted amino acid
What is Teprotide?
Why does teprotide have limited use + wasn’t brought into the market?
How did teprotide help with the development of succinyl-proline
Nonapeptide isolated from the venom of the brazilian pit viper
ACE inhibitor
Teprotide is orally inactive - susceptible to digestive enzymes
From this researchers conducted structure-activity studies which allowed them to identify the active binding site of the ACE
Proline was found to be involved in binding interactions with binding site
Proline was chosen as the amino acid for the succinyl-substitued amino acid
Succinyl-proline is shown to be a weak, but selective, ACE inhibitor
How was captopril developed?
Modified succinyl-proline by:
- adding CH3 group - form additional hydrophobic interactions with S1’ pocket (extension strategy)
- adds another assymmetric centre
- carboxylate group replaced with thiol (-SH) - forms stronger interactions with zinc ion
Captopril is the 1st non-peptide ACE inhibitor to be marketed
What are the disadvantages of captopril?
Common side effects are rashes and loss of taste
Side effects thought to be associated with the thiol group
Replacement of thiol group with carboxylate group likely to decrease side effects, but lead to a drop in activity
Need to introduce further binding interactions to compensate - extension strategies
Describe the design of enalaprilate
Which functional groups fit into the S1 + S1’ pockets?
What is enalapril?
Carboxylate ion acts as zinc binding group
Weaker interaction than a thiol group
Compensated by extra binding interactions involving phenethyl, amine and methyl groups
Amine introduced to mimic binding interactions of amide NH in substrate
Methyl group fits S1’ pocket
Phenethyl group fits S1 pocket
Enalapril = ethyl ester prodrug for enalaprilate
Describe the design of Lisinopril
Similar to enalaprilate
Longer amine group
What are transition-state inhibitors?
e.g. enalaprilate + lisinopril
They mimic the enzyme reaction in one other way
