strategy behind the development of captopril? and how it involved combining a proline amino acid with a benzyl succinic acid derivative?
1. The H on the 1st carboxyl group replaced with proline
2. C-benzyl ring replaced with methyl group (CH3)
3. 2nd carboxyl group replaced with thiol (SH)/sulfhydrl group
angiotensinogen (Renin) --> angiotensin I (ace) --> angiotensin II --> AT1 (or AT2)
- rate limiting step is renin
All ACEI are have prodrugs except?
captopril and lisinopril
what prodrugs in ACEI are necessary?
-pril --> prilat
-Prodrugs will cross membrane for absorption
what does logP (greasiness) actually mean?
-logP is asking if the drugs prefers the lipid soluble or water soluble phase
-high logP will give a high number/1 = lipid soluble/hydrophobic/non-polar/(greasy lol)
- low logP will give a low number/1 = water solube/hydrophilic/polar
How do you predict the basicity of amines?
based on the if the lone pair of electrons interact with the structure. If it does then it is a weak base
ACE inhibitors may be divided up into three subclasses based on the functional groups that interact with Zn(II) ion what group does captopril fall in?
thiol/sulfhydryl ( SH)
ACE inhibitors may be divided up into three subclasses based on the functional groups that interact with Zn(II) ion what group does Fosinopril fall in?
ACE inhibitors may be divided up into three subclasses based on the functional groups that interact with Zn(II) ion what group does all other ACEIs fall in?
di-carboxylic acid (COOH x 2)
how is benazipril metabolized?
what is significant about the N in moexipril structure?
closer to the double bond of a ring is less basic because its lone pair of electron will interact with the benzene ring
the more rings or carbons a structure make it?
more double bonds in ring have what effect on the pKa?
lower PKa (trandolapril)
the equilibrium with chlorathalidone has to do with what structure?
-phalalalimidine to a benzophenone (closed ring to a benzyl ring connected to two carbonyl groups):
1. nitrogen can attack the carbonyl carbon and form the benzophenone OR
2. the functional group can re arrange to give the ketone and amide nitrogen back
historical relationship to the early sulfa drugs related to diuretics?
-prontisil (prodrug) is a red dye that has antibacterial properties lead to the first sulphanilamide. N=N double bond is called an azo group. Sulphanilamide is a mimic of PABA (paraaminobenzoic acid...how bacteria consume folic acid)
- NH2 resembles PABA and the sulfonamide group resembles a carboxylate group (b/c of the two oxygens) and loses the H+ easily