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PDAT5 CV > 9/10 - Chemistry of Anti-HT's > Flashcards

9/10 - Chemistry of Anti-HT's Flashcards

1
Q

Selective B1-Adrenergic Antagonist

Features

A

PARA substituent = B1 Selective

3A-2B-E-M

Atenolol + Acebutolol + Alprenolol

Betaxolol + Bisoprolol

Esmolol

METOPROLOL

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2
Q

What Drug & What Class?

A

VERAPAMIL
Calcium Channel Blocker

PhenylAlkylAmine = PAA

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3
Q

What Drug?

A

CAPTOPRIL

look at the:
SULFA GROUP
essential for chelating the ZINC ion of the enzyme

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4
Q
  • *Lead Compound for ARBs**
  • *ImidazoleAcetic Acid = Lead Compound**

Correlation with AT2:
Tyr 4

A

PHENYL RING

mimics the:
Tyr 4
side chain of AT2

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5
Q

Diltiazem

Drug Class & PK/PD

A

BenzoThiazepine = BTZ
Calcium Channel Blocker

  • *Single (+) Enantiomer**
  • *Fast Onset** due to HIGH LIPID Solubility

Extensive Metabolism into ACTIVE:
DaAcetyl-Diltiazem

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6
Q

What Drug?

A

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

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7
Q

What is normally on the
RING?
&
What site does it bind to?

DiCarboxylate-Containing ACE-Inhibitors​

A

Ring:
CarboCyclic AA** –> **S2’ Site
needed for the terminal peptide residue

VARIES for each ACE-I
Cyclic + -COOH

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8
Q

Which B-Blockers have
INTRINSIC SYMPATHOMIMETIC ACTIVITY
(ISA)?

What FEATURE do we look for?

A

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

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9
Q

What Drug & Class?

A

DILTIAZEM
Calcium Channel Blocker

BTZ** = **BenzoThiAzePine

Benzo = Benzyne

Thio = Sulfur

Aza = Nitrogen

Pine = 7 membered ring

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10
Q

Verapamil

Metabolism

A

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

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11
Q

SAR of 1,4-DHPs

What is preferred on the X group?

A

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

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12
Q

CCB’s
Mechanism of Action

A

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

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13
Q
  • *What drugs are**
  • *Centrally Acting a2-agonists?**
A

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

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14
Q

1,4-DHP SAR

R6 or C6
changes

A
  • *R6** can tolerate
  • *LARGER SUBSTITUENTS**

Since Amlodipine = Enhanced Potency

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15
Q

SARs of ARBs

Eprosartan

A

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

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16
Q

SAR of CAPTOPRIL

A

Methyl Group Stereoconfiguration
important –> mimics the L-Amino Acid

SULFA GROUP
essential for chelating the ZINC ion
but also produced:
SKIN RASH + TASTE DISTURBANCE

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17
Q

What Drug?

A

CANDESARTAN CILEXETIL
&
Olmesartan Medoxomil

both are:
rapidly & completely metabolizeed @ INTESTINAL WALL

= PRODRUG
to increase oral bioavailability

Oxygen-Carbon-Oxygen = Good Leaving Group

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18
Q

ACE-Independent Pathways

Avoid Renin & ACE

A

Cathepsin G

Trypsin

Kallikrein

Chymase

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19
Q

Discovery of PROPRANOLOL

Non-Selective B-Adrenergic Antagonist

A

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**
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20
Q

Newer 1,4-DHPs

R vs S

A

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

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21
Q

Lead Compound for ARBs
ImidazoleAcetic Acid

Correlation with AT2:
His 6

A

IMIDAZOLE RING

overlaps with the:
His 6
side chain

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22
Q

Diltiazem = BTZ
Where does it enter?
&
​Binding Site?

A

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

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23
Q

1,4-DHP

Essential SAR’s

A
  • *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

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24
Q

What Drug & Class?

A

METOPROLOL
Selective B1-Adrenergic Antagonist

Para-Substituent

25
**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*
26
**_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**
27
**What Drug & Class?**
**_PROPRANOLOL_** **Non-Selective** B-Adrenergic Antagonist S-Active ## Footnote **Lipid Soluble --\> crosses BBB --\> *CNS SIDE EFFECTS***
28
**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
29
**What Drug?**
* *_LOSARTAN_** * *ARB** Major Change was the addition of the: **Di-Phenyl Ring**
30
**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*
31
**Signals for RENIN RELEASE**
**_HemoDynamic Signals_** ↓**Glomerular Filtration** * *_Neurogenic Signals_** * *B1- receptor** activation * *_Humoral Signals_** * *VIP** - **Glucagon** - **PTH**
32
**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**
33
**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**
34
**METABOLISM** of **DiCarboxylate-Containing ACE-I**
**_RENAL ELIMINATION_** primary route for most ACE-inhibitors *except for* **_*FOSINOPRIL***_ _***& SPIRAPRIL*_** **_Cyclization**_ --\> _**Diketopiperazine_** for **R**amipril / **P**erindopril / **M**oexipril
35
**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
36
**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**
37
**Diltiazem = BTZ** **METABOLISM**
Extensive Metabolism​ by: **_Ester Hydrolysis_** to form the **ACTIVE METABOLITE: _DeAcetyl-Diltiazem_** Then **_O- & N- Demehylations_** by **_CYP3A4_** to ***inactive metabolites***
38
**Losartan** **METABOLISM**
**_CYP2C9**_ & _**CYP3A4_** 14% is oxidized to produce an **Active Metabolite = _EXP-3174_** **10-40x more potent** than **losartan** The o**verall cardiovascular effects** seen with losartan is due to the **combined actions of the parent drug and the active metabolites.**
39
**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***
40
**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_**
41
**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**
42
**What is normally on the _R2_?** & **What site does it bind to?** ## Footnote **DiCarboxylate-Containing ACE-Inhibitors​**
R2: **_ETHYL GROUP_** except for: **Lisinopril = H** Basic Amino group that creates an IONIC interaction **R1 = (CH2)4NH2** + **H = R2**
43
**What is normally on the _R3_?** & **What site does it bind to?** ## Footnote **DiCarboxylate-Containing ACE-Inhibitors​**
R3: **_PHENYL**_ --\> _**S1 Site_** * *MOST IMPORTANT - -\> OVERCOMES WEAK BINDING *w/o* STRONG ZINC-INTERACTION** all except for: **Perindopril = CH3**
44
**What is normally on the _R1_?** & **What site does it bind to?** ## Footnote **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**
45
**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**
46
**Lead Compound for ARBs** ImidazoleAcetic Acid Correlation with **AT2**: **_Phe 8_**
**_Ionized Carboxylate Group_** - -\> **Phe 8** * *C-terminal Carboxylate of AT2**
47
**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*
48
**Lead Compound for ARBs** ImidazoleAcetic Acid Correlation with **AT2**: **_Ile 5_**
**_N-Butyl Group_** * *Hydrocarbon Side Chain** of * *Ile 5**
49
**What converts AT2** --\> **AT3**?
**_AMINOPEPTIDASE_** AT2 -\> AT3
50
**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
51
**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**
52
**_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**
53
**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**
54
**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
55
**What is the RATE LIMITING step of the: RAAS System?**
* *_RENIN_** * *Angiotensinogen** --\> **Angiotensin 1**
56
**What Drug & Class?**
**_ATENOLOL_ Selective B1-**Adrenergic Antagonist * *Para-Substituent =** **CONH2** * *More Hydrophilic --\> *_less CNS side effects_*** * cant cross BBB*
57
* *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*
58
**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

PDAT5 CV (30 decks)

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