9/10 - Chemistry of Anti-HT's Flashcards
Selective B1-Adrenergic Antagonist
Features
PARA substituent = B1 Selective
3A-2B-E-M
Atenolol + Acebutolol + Alprenolol
Betaxolol + Bisoprolol
Esmolol
METOPROLOL
What Drug & What Class?
VERAPAMIL
Calcium Channel Blocker
PhenylAlkylAmine = PAA
What Drug?
CAPTOPRIL
look at the:
SULFA GROUP
essential for chelating the ZINC ion of the enzyme
- *Lead Compound for ARBs**
- *ImidazoleAcetic Acid = Lead Compound**
Correlation with AT2:
Tyr 4
PHENYL RING
mimics the:
Tyr 4
side chain of AT2
Diltiazem
Drug Class & PK/PD
BenzoThiazepine = BTZ
Calcium Channel Blocker
- *Single (+) Enantiomer**
- *Fast Onset** due to HIGH LIPID Solubility
Extensive Metabolism into ACTIVE:
DaAcetyl-Diltiazem
What Drug?
AZILSARTAN MEDOXOMIL
ProDrug –> completely metabolized @ Intestinal Wall
- *Tetrazole Ring** –> REPLACED by a OXO-OXADIAZOLE RING
- LESS ACIDIC*
better control of 24 hour SBP than other ARB’s
Better AT1 Binding
&
DISSOCIATES more SLOWLY
vs other ARBS
What is normally on the
RING?
&
What site does it bind to?
DiCarboxylate-Containing ACE-Inhibitors
Ring:
CarboCyclic AA** –> **S2’ Site
needed for the terminal peptide residue
VARIES for each ACE-I
Cyclic + -COOH
Which B-Blockers have
INTRINSIC SYMPATHOMIMETIC ACTIVITY
(ISA)?
What FEATURE do we look for?
ISA = C-A-PP
Carteolol - Acebutolol - Pindolol - Penbutolol
- *NH_ or _OH** @ Meta/Para of Phenyl Ring
- via metabolic biotransformation*
allowing them to:
Partially Stimulate the B-Receptor
What Drug & Class?
DILTIAZEM
Calcium Channel Blocker
BTZ** = **BenzoThiAzePine
Benzo = Benzyne
Thio = Sulfur
Aza = Nitrogen
Pine = 7 membered ring
Verapamil
Metabolism
More Active S (-) Isomer –> rapidly N-demethylated by
CYP3A4
in intestine & liver into:
NORVERAPAMIL (~20% potency of Verapamil)
Verapamil is also a substrate of:
P-GLYCOPROTEIN EFFLUX TRANSPORTER
which will drastically
INCREASE Intestinal Absorption or other P-gp substrates
like digoxin, in a dose-dependent manner
SAR of 1,4-DHPs
What is preferred on the X group?
BULKY GROUP in Ortho / Meta
in order to
LOCK conformation of the 1,4-DHP so that:
2 RINGS are PERPENDICULAR to one another
X:
Nifedipine / Nosoldipine = 2-NO2
Amlodipine = 2-Cl
CCB’s
Mechanism of Action
with the exception of BEPRIDIL:
CCBs are selective for:
L-Type High-Voltage-Activated Calcium Channels
Most effective when membrane depolarization is:
Longer / More Intense / More Frequent
USE-DEPENDENCY
indicate that CCBs prefer to interact with theire receptors in the
CA channel in either the states of either:
OPEN**or**INACTIVE
- *What drugs are**
- *Centrally Acting a2-agonists?**
L-MethylDopa** + **Clonidine** + **Guanfacine** + **Guanabenz
Clonidine
metabolized in liver –> glucuronide/sulfate conjugates
Guanfacine
more selective for a2 receptor > clonidine or guanabenz
liver metabolized –> glucoronide/sulfate/mercapturic acid
1,4-DHP SAR
R6 or C6
changes
- *R6** can tolerate
- *LARGER SUBSTITUENTS**
Since Amlodipine = Enhanced Potency
SARs of ARBs
Eprosartan
ACIDIC GROUP
needed to mimic the Tyr4 Phenol
CARBOXYLATE GROUP** @ **ORTHO POSITION
for optimal activity
THIENYL METHYL SIDE CHAIN
provided a better mimic of Phe 8
SAR of CAPTOPRIL
Methyl Group Stereoconfiguration
important –> mimics the L-Amino Acid
SULFA GROUP
essential for chelating the ZINC ion
but also produced:
SKIN RASH + TASTE DISTURBANCE
What Drug?
CANDESARTAN CILEXETIL
&
Olmesartan Medoxomil
both are:
rapidly & completely metabolizeed @ INTESTINAL WALL
= PRODRUG
to increase oral bioavailability
Oxygen-Carbon-Oxygen = Good Leaving Group
ACE-Independent Pathways
Avoid Renin & ACE
Cathepsin G
Trypsin
Kallikrein
Chymase
Discovery of PROPRANOLOL
Non-Selective B-Adrenergic Antagonist
Isoproternol
replaced the catechol –> CHLORINE = Sympatholytic Agent (DCI)
Pronethalol (R-isomer)
ELONGATION of ETHYLAMINE by an OXYMETHYLENE BRIDGE
& placement @ C1 POSITION of the Naphthyl Group
- *PROPRANOLOL**
- *S- Isomer Active**
Newer 1,4-DHPs
R vs S
Replacement @ C3 or C5
Ester –> NO2
Produces a pair of STEREOISOMERS with Opposite actions
R (-)- PN202-791 blocks the calcium channel
R - Block
S (+)- PN202-791 activates the calcium channel
by stabilizing the channel in the open state during depolarization
potential use for the S (+) isomer for Congestive Heart Failure
Lead Compound for ARBs
ImidazoleAcetic Acid
Correlation with AT2:
His 6
IMIDAZOLE RING
overlaps with the:
His 6
side chain
Diltiazem = BTZ
Where does it enter?
&
Binding Site?
1,4-DHPs & Diltiazem enter from the
EXTRACELLULAR SIDE
Binding of Diltiazem or 1,4-DHP in the ALLOSTERIC interacting site:
INHIBIT’s the binding of VERAPAMIL
Diltiazem + 1,4-DHPs = POSITIVE ALLOSTERIC EFFECTORS
enhance the binding of each other
1,4-DHP
Essential SAR’s
- *Ester Groups_ @ _C3_ & _C5**
- replacement with another group –> ENANTIOMERIC isomers*
O** or **M-substituted Phenyl Ring** @ **C4 Position
provides optimal CCB activity = 90*
Size of Substituent X is important
sufficient BULK –> to LOCK conformation of 1,4-DHP
so that
2 Rings are PERPENDICULAR to ONE ANOTHER
What Drug & Class?
METOPROLOL
Selective B1-Adrenergic Antagonist
Para-Substituent
SARs of ARBs
Valsartan
ACIDIC GROUP
needed to mimic the Asp1 Carboxylate of AT2
TETRAZOLE** @ **ORTHO POSITION
for optimal activity
Tetrazole = bioisosteric replacement for carboxylate group has
superior:
metabolic stability / lipophilicity / oral BioAvailability
than other carboxylate analogues
Hepatic Esterase
Function?
All dicarboxylated-containing ACE-Inhibitors are:
PRODRUGS
to ↑Oral BioAvailability
EXCEPT FOR LISINOPRIL
Ester is CLEAVED –> -COOH can bind to ZINC
Enalaprilat is 10x more potent
due to presence of phenylethyl R3 side chain –> S1 Binding
What Drug & Class?
PROPRANOLOL
Non-Selective B-Adrenergic Antagonist
S-Active
Lipid Soluble –> crosses BBB –> CNS SIDE EFFECTS
What Drug & Class?
- *L-Methyldopa**
- *Centrally Acting a2-agonist**
Pro-drug –> crosses BBB via L-aromatic AA transporter
Converted in the CNS by:
L-Aromatic AA decarboxylase & Dopamine B-hydroxylase
into:
A-methylNorEpinephrine
undergoes FIRST PASS metabolism in GI TRACT
What Drug?
- *LOSARTAN**
- *ARB**
Major Change was the addition of the:
Di-Phenyl Ring
What Drug & Class?
- *HYDRALAZINE**
- *Arterial Vasodilator**
Well absorbed from the GI Tract
Extensive metabolism @ GI mucosa & liver
by:
acetylation / hydroxylation / conjugation w-glucuronic acid
used in pregnancy
Signals for RENIN RELEASE
HemoDynamic Signals
↓Glomerular Filtration
- *Neurogenic Signals**
- *B1- receptor** activation
- *Humoral Signals**
- *VIP** - Glucagon - PTH
Verapamil = PAA
Where does it enter?
&
Binding Site?
Verapamils enter the Ca Channel from the:
CYTOPLASMIC SIDE
binding to Allosteric Interacting Site leads to:
Inhibits the binding of both:
DILTIAZEM & 1,4-DHPs
Verapamil = NEGATIVE ALLOSTERIC EFFECTOR
Discovery of CAPTOPRIL / ACE Inhibitors
Main Compounds
Teprotide
from snake venom, –> drop in BP due to ACE inhibition
Ace similar to:
digestive pancreatic Carboxipeptidase A
ZINC-dependent monopeptidyl carboxypeptidase
D-2-Benzylsuccinic Acid
found to be a potent INHIBITOR of Carboxipeptidase A
2nd carboxylate group–> bind to zinc @ active site
METABOLISM
of
DiCarboxylate-Containing ACE-I
RENAL ELIMINATION
primary route for most ACE-inhibitors
except for
FOSINOPRIL** **& SPIRAPRIL
Cyclization** –> **Diketopiperazine
for
Ramipril / Perindopril / Moexipril
What Drug?
Special Use?
- *CLEVIDIPINE**
- *Lipophilic**, Short-Acting 1,4-DHP CCB
OIL-IN-WATER EMULSION –> IV USE
Metabolized by:
Blood & Tissue Esterases
1-2 min Half Life
Actions of
AT1 Receptor Binding
AT receptors are G__PCR’s
Kidneys
↑Na+/H2O reabsorption
↓GFR
Adrenals
↑Aldosterone / ↑Catecholamines
Vascular Smooth Muscle
VasoConstriction
Myocardium
↑Contractility / ↑Hypertrophy
↓Collagenase
CNS
↑ADH↑Thirst ↑Adrenal Drive
Diltiazem = BTZ
METABOLISM
Extensive Metabolism by:
Ester Hydrolysis
to form the ACTIVE METABOLITE:
DeAcetyl-Diltiazem
Then
O- & N- Demehylations by CYP3A4
to inactive metabolites
Losartan
METABOLISM
CYP2C9** & **CYP3A4
14% is oxidized to produce an
Active Metabolite = EXP-3174
10-40x more potent than losartan
The overall cardiovascular effects seen with losartan is due to the combined actions of the parent drug and the active metabolites.
What Drug & Class?
BEPRIDIL
Calcium Channel Blocker
DIAMINOPROPANOL ETHER
no longer on the market due to VENTRICULAR ARRYTHMIA
NOT selective for L-type high-voltage activated CCB’s
Non-Selective B-Adrenergic Antagonists
Features
- *Lipid Soluble –> BBB cross –> CNS SIDE EFFECTS**
- dizziness / confusion / depression*
3P-N-T + C
Propranolol + Pindolol + Penbutolol“All P’s”
**_Nadalol_** more hydrophilic (-OH)
Timolol
Carteolol
Which drugs are
MIXED A/B Adrenergic Antagonist?
LABETALOL** + **CARVEDILOL
- *Labetalol = 4 stereoisomers**
- *R, R-diastereomer** = nonselective b antagonist + partial b2 agonism
- *R, S-diastereomer = a1-antagonist activity**
- without any effect on the b receptors.*
Carvedilol = Racemate
S(-) enantiomer = BOTH a & non-selective B-antagonist
R(+) enantiomer = a1 antagonist
What is normally on the
R2?
&
What site does it bind to?
DiCarboxylate-Containing ACE-Inhibitors
R2:
ETHYL GROUP
except for:
Lisinopril = H
Basic Amino group that creates an IONIC interaction
R1 = (CH2)4NH2 + H = R2
What is normally on the
R3?
&
What site does it bind to?
DiCarboxylate-Containing ACE-Inhibitors
R3:
PHENYL** –> **S1 Site
- *MOST IMPORTANT
- -> OVERCOMES WEAK BINDING w/o STRONG ZINC-INTERACTION**
all except for:
Perindopril = CH3
What is normally on the
R1?
&
What site does it bind to?
DiCarboxylate-Containing ACE-Inhibitors
R1:
METHYL GROUP** –> **S1’ Site
except for:
Lisinopril = (CH2)4NH2
Basic Amino group that creates an IONIC interaction
R1 = (CH2)4NH2 + H = R2
What drug requires you to take
ONE HOUR BEFORE MEALS?
and WHY?
CAPTOPRIL
Because most protein in your food has:
CYSTEINE
which will break down / metabolize the captopril
into:
Captopril-Cysteine Disulfide metabolite
Lead Compound for ARBs
ImidazoleAcetic Acid
Correlation with AT2:
Phe 8
Ionized Carboxylate Group
- -> Phe 8
- *C-terminal Carboxylate of AT2**
Metabolism & Drug Interactions
of 1,4-DHPs
hepatic CYP3A4 –> inactive pyridine metabolites
Nisoldipine –> side Chain hydroxylation @ isobutyl ester
also by CYP3A4
GRAPEFRUIT JUICE
↑Systemic Concentration
Furanocoumarines –> inhibition of CYP3A4 isozymes
Lead Compound for ARBs
ImidazoleAcetic Acid
Correlation with AT2:
Ile 5
N-Butyl Group
- *Hydrocarbon Side Chain** of
- *Ile 5**
What converts AT2 –> AT3?
AMINOPEPTIDASE
AT2 -> AT3
Verapamil
Drug Class & PK/PD
PAA** = **PhenylAlkylAmine
RACEMATE
half life of ~ 7 hours
LOW BioAvailability +HIGH ORAL absorption=High First Pass
due to High LIPID solubility –> peak conc. @ 1-2 hours
Gallopamil
another PAA marketed for prophylaxis & long-term therapy of:
CHD & Atrial TachyArrythmia
Which drug is a:
PHOSPHONATE-Containing ACE-I?
FOSINOPRIL
- instead of Carboxylate group or Sulfhydryl in the N-Ring*
- *PhosPhinic Acid Moety_ –> _Zinc Ion**
Ionized Phosphonic Acid
mimics the TETRAHEDRAL Intermediate
of peptide hydrolysis
Highest ACE Affinity
2 Important SARs
of DiCarboxylate-Containing ACE-Inhibitors
N-Ring must contain a:
Carboxylic Acid** w/ a **S-Configuration
mimics the C-Terminal Carboxylate of ACE substrate
To avoid Captopril’s SULFUR ADR –> use Carboxylic Acid to CHELATE the ZINC ion
&
Large Hydrophobic HETEROcyclic Ring
in the N-ring
↑Potency & ↑PK parameters
What Drug?
ALISKIREN
Tekturna
RENIN INHIBITOR
(Rate limiting step in RAAS system)
- can NOT be used in combination with:*
- *ARBS or ACEi’s** for patients with DIABETES
Azilartan Medoxomil
What Improvements?
ProDrug –> completely metabolized @ Intestinal Wall
- *Tetrazole Ring** is REPLACED by a
- OXO-OXADIAZOLE RING** = *_LESS ACIDIC_
better control of 24 hour SBP than other ARB’s
Better AT1 Binding
&
DISSOCIATES more SLOWLY
vs other ARBS
What is the RATE LIMITING step of the:
RAAS System?
- *RENIN**
- *Angiotensinogen** –> Angiotensin 1
What Drug & Class?
ATENOLOL
Selective B1-Adrenergic Antagonist
- *Para-Substituent =** CONH2
- *More Hydrophilic –> less CNS side effects**
- cant cross BBB*
- *ACE**
- *Function & Structural Requirements**
- relatively non-specific enzyme*
- *ZINC-dependent DiPeptidyl Carboxypeptidase**
- cleaves 2 AA’s on CARBOXY side*
- *AT1 –> AT2**
Bradykinin
is also INACTIVATED by ACE
required feature:
- *PENULTIMATE AA Residue** = TriPeptide or larger
- can NOT be PROLINE*
- this is why AT2 is NOT further metabolized by ACE*
1,4-DHPs
Where does it enter?
&
Binding Site?
1,4-DHPs & Diltiazem enter from the
EXTRACELLULAR SIDE
and prefer to bind in the Ca-Channel’s
INACTIVATED STATE
Binding of Diltiazem or 1,4-DHP in the ALLOSTERIC interacting site:
INHIBIT’s the binding of VERAPAMIL
Diltiazem + 1,4-DHPs = POSITIVE ALLOSTERIC EFFECTORS
enhance the binding of each other
