Randal A. SkidgelRandal A. Skidgel ACE Inhibitors

From: Skidgel and Erdös, AHA Hypertension Primer, 2008

ACE Inhibitors

ACE = Angiotensin I Converting Enzyme

10 ACE inhibitors available in US: benazepril, captopril, enalapril, fosinopril, lisinopril,

moexipril, perindopril, quinapril, ramipril and trandolapril.

ACE inhibitors were the 4th most prescribed drug class in the U.S (159.8 million Rx in 2008).

Lisinopril was the 2nd most prescribed drug in the US (75.5 million Rx in 2008).

The Renin-Angiotensin and Kallikrein-Kinin Systems

From: Skidgel RA and Erdös EG, Hypertension Primer, 4th Edition, Chap. A15, 2008.

Some Biologically Active PeptidesACTHACTH

AdrenomedullinAdrenomedullin

ß-Amyloid(1-40)ß-Amyloid(1-40)

Anaphylatoxins Anaphylatoxins

Angiotensin II Angiotensin II

Angiotensin(1-7) Angiotensin(1-7)

Atrial Natriuretic Peptide Atrial Natriuretic Peptide

BAM-12P, 18P & 22PBAM-12P, 18P & 22P

BombesinBombesin

Bradykinin Bradykinin

Brain Natriuretic PeptidesBrain Natriuretic Peptides

BuccalinBuccalin

Bursin Bursin

C-Type Natriuretic Peptide C-Type Natriuretic Peptide

Caerulein Caerulein

Calcitonin Calcitonin

Calcitonin Gene RelatedPeptideCalcitonin Gene RelatedPeptide

CardiodilatinCardiodilatin

CarnosineCarnosine

CASH (Cortical Androgen- Stimulating CASH (Cortical Androgen- Stimulating Hormone)Hormone)

CasomorphinsCasomorphins

CerebellinCerebellin

Cholecystokinin Cholecystokinin

ChromostatinChromostatin

CLIPCLIP

Contraceptive TetrapeptideContraceptive Tetrapeptide

Corticotropin Inhibiting PeptideCorticotropin Inhibiting Peptide

CorticostatinCorticostatin

Corticotropin ReleasingFactor Corticotropin ReleasingFactor

CytokinesCytokines

Delta Sleep-Inducing PeptideDelta Sleep-Inducing Peptide

Dermorphin Dermorphin

Dermaseptin Dermaseptin

Diabetes-Associated PeptideDiabetes-Associated Peptide

Diazepam Binding Inhibitor Diazepam Binding Inhibitor

Dynorphins Dynorphins

ß Endorphin ß Endorphin

Endothelins Endothelins

Met‑Enkephalin Met‑Enkephalin

Leu‑Enkephalin Leu‑Enkephalin

Epidermal Mitosis Inhibiting Peptide Epidermal Mitosis Inhibiting Peptide

ErythropoietinErythropoietin

Follicle Stimulating Hormone Follicle Stimulating Hormone

GalaninGalanin

Gastric Inhibitory Polypeptide Gastric Inhibitory Polypeptide

Gastrin Gastrin

Gastrin-Releasing PeptideGastrin-Releasing Peptide

α-Gliadorphinα-Gliadorphin

Granuliberin-RGranuliberin-R

Glucagon Glucagon

Glucagon-Like PeptideGlucagon-Like Peptide

Growth Factors Growth Factors

Growth HormoneGrowth Hormone

Growth Hormone‑ ReleasingHormone Growth Hormone‑ ReleasingHormone

GuanylinGuanylin

Inhibin Inhibin

Insulin Insulin

InterleukinsInterleukins

Kallidin Kallidin

KyotorphinKyotorphin

α & ß-Lactorphinα & ß-Lactorphin

Leucokinins Leucokinins

LipotropinLipotropin

Luteinizing Hormone (LH)Luteinizing Hormone (LH)

LH‑Releasing HormoneLH‑Releasing Hormone

MagaininsMagainins

MastoparanMastoparan

Melanin-ConcentratingMelanin-Concentrating

HormoneHormone

α‑Melanocyte Stimulatingα‑Melanocyte Stimulating

Hormone Hormone

MelanostatinMelanostatin

Morphine ModulatingMorphine Modulating

NeuropeptideNeuropeptide

MotilinMotilin

α‑Neoendorphinα‑Neoendorphin

ß‑Neoendorphinß‑Neoendorphin

Neurokinin ANeurokinin A

Neurokinin BNeurokinin B

Neuromedin NNeuromedin N

Neuropeptide YNeuropeptide Y

Neuropeptide PNeuropeptide P

ß-Neuroprotectinß-Neuroprotectin

NeurotensinNeurotensin

Neutrophil DefensinsNeutrophil Defensins

OrexinsOrexins

OxytocinOxytocin

PACAP (Pituitary Adenylate Cyclase Activating PACAP (Pituitary Adenylate Cyclase Activating Peptide)Peptide)

PancreastatinPancreastatin

Pancreatic PolypeptidePancreatic Polypeptide

Parathyroid HormoneParathyroid Hormone

Peptide Histidine IsoleucinePeptide Histidine Isoleucine

Peptide YYPeptide YY

ProlactinProlactin

ProctolinProctolin

RiginRigin

SecretinSecretin

SomatostatinSomatostatin

Substance PSubstance P

SysteminSystemin

ThymosinThymosin

ThyrotropinThyrotropin

Thyrotropin ReleasingThyrotropin Releasing

HormoneHormone

TuftsinTuftsin

UrocortinUrocortin

UroguanylinUroguanylin

Vasopressin (ADH)Vasopressin (ADH)

VIP (Vasoactive IntestinalVIP (Vasoactive Intestinal

Peptide)Peptide)

Prohormone

Peptidase 1

RK RR

Endoprotease

Active Peptide

Processing Enzyme

Receptor 1Receptor 2

Peptidase 2

Scheme of Peptide Hormone Processing & Metabolism

Strategies for Developing Therapeutic Agents

Peptidase 1

Active Peptide

Receptor 1Receptor 2

Peptidase 2

Administer the Peptide

Use of Peptides as Drugs

Advantages Highly potent/excellent specificity Wide variety of Biological Activities Straightforward Synthesis Predictable Chemistry Little or no toxicity from metabolism

Disadvantages Oral administration difficult because of:

Degradation by digestive enzymes and intestinal peptidases Poor absorption across tight junctions in epithelila Efflux systems may pump absorbed peptides back out

Inconvenient administration Rapidly cleaved by peptidases Excreted by kidney Relatively expensive to synthesize compared with small organic

molecules

Peptidase 1

Receptor 1Receptor 2

Peptidase 2

Block Degradation by Peptidases

Strategies for Developing Therapeutic Agents

Strategies for Developing Therapeutic Agents

Peptidase 1

Active Peptide

Receptor 1Receptor 2

Peptidase 2

Use a Receptor Antagonist

Prohormone

Peptidase 1

RK RR

Endoprotease

Active Peptide

Processing Enzyme

Receptor 1Receptor 2

Peptidase 2

Block Synthesis/Processing

Strategies for Developing Therapeutic Agents

ACE

ACE DISTRIBUTION

Widespread, concentrated on:

•Endothelial surface of the vasculature

•Epithelial Brush borders

•Renal proximal tubules

•Small intestine

•Placenta

•Choroid plexus

Structure of Human Angiotensin Converting Enzyme (ACE)

ACE

ACE

C-domain

N-domain

A given peptidase can cleave a variety of peptidesExample: Angiotensin Converting Enzyme (ACE)

Structures of Clinically Used ACE Inhibitors

Angiotensinogen

Renin

Angiotensin I (Inactive)

Blood Pressure

Kininogen

Kallikrein

Bradykinin Kinin B2 Receptor

Vasodilation

Na+ Excretion

Bradykinin(1-7) (Inactive)

ACE

ACE Inhibitors

Mechanism of Action of ACE Inhibitors

Angiotensin II

AT1 Receptor

VasoconstrictionAldosterone release

Na+ RetentionPro-inflammatory

Oxidative stress

Angiotensinogen

Renin

Angiotensin I (Inactive)

Angiotensin II

AT1 Receptor

Blood Pressure

Endopeptidases

Angiotensin 1-7 AT1-7/Mas Receptor

Angiotensin 1-5 (Inactive)

ACE

ACE Inhibitors

Mechanism of Action of ACE Inhibitors II

VasodilationNa+ ExcretionAnti-inflammatory Oxidative stress

VasoconstrictionAldosterone release

Na+ RetentionPro-inflammatory

Oxidative stress

Clinical Use of ACE Inhibitors

Antihypertensive ~ 50% response (~90% with diuretic) ↓Systemic Vascular Resistance ↓Stress or Relfex induced sympathetic stimulation → Heart rate ↑ Sodium excretion, ↓ Blood volume

Congestive Heart Failure ↓Vascular Resistance, Blood volume, Heart rate ↑ C.O. (no change in myocardial O2 consumption)

Diabetic Nephropathy Dilates afferent and efferent renal arterioles ↓Glomerular capillary pressure ↓Growth of mesangial cells/matrix due to Ang II?

Side Effects/Contraindications

Common Dry Cough

5 – 20% of patients Not dose-related; occurs within 1 wk. – 6 mo. Women > men May Require cessation of therapy

Fetopathic Potential Not teratogenic in 1st trimester Developmental defects in 2nd or 3rd trimester

Rare Angioneurotic Edema (or Angioedema)

~0.1 - 0.5% of patients Not dose-related; occurs within 1st week Severe swelling of mouth, tongue, lips, airway may be life-threatening

Side Effects/Contraindications

Rare Hypotension

First dose effect in patients with elevated PRA, salt depletion, CHF

Hyperkalemia In patients with renal insufficiency, diabetic nephropathy

Acute Renal Failure Patients with renal stenosis, heart failure, volume depleted

Skin Rash

Extremely Rare (reversible) Alteration/loss of taste Neutropenia Glycosuria Hepatotoxicity

Drug Interactions

Antacids May reduce bioavailability of ACE inhibitors

Capsaicin May worsen ACE inhibitor-induced cough

NSAIDs May reduce antihypertensive response to ACE inhibitors

K+-sparing Diuretics or K+ supplements May exacerbate ACE inhibitor-induced hyperkalemia

Additional Beneficial Effects of ACE Inhibitors

Cardioprotective

Reduce incidence of second heart attack Reduce cardiovascular complications in patients

with risk factors

Reduce incidence of diabetes in high risk patients

Reduce complications in diabetic patients

Novel and Unexpected Functions of ACE and ACE inhibitors

ACE inhibitors induce protein crosstalk between ACE and ACE inhibitors induce protein crosstalk between ACE and bradykinin B2 receptor, enhancing signaling.bradykinin B2 receptor, enhancing signaling.

ACE inhibitors are direct agonists of the B1 kinin GPCR and ACE inhibitors are direct agonists of the B1 kinin GPCR and induce endothelial nitric oxide production.induce endothelial nitric oxide production.

ACE inhibitor binding to ACE itself activates the MAP kinase ACE inhibitor binding to ACE itself activates the MAP kinase JNK and stimulates gene transcription.JNK and stimulates gene transcription.

See: Erdös EG, Tan F, and Skidgel RA. Angiotensin I-converting enzyme inhibitors are allosteric enhancers of kinin B1 and B2 receptor function. Hypertension 55: 214-220, 2010

ACE

KininogenAngiotensinogen

Renin Kallikrein

Angiotensin I (Inactive)

Bradykinin B2 Receptor

AT1 Receptor

Angiotensin II

Vasoconstriction

Aldosterone release

Na+ Retention

Bradykinin(1-7) (Inactive)

Blood Pressure

AngiotensinReceptor

Antagonists(the “sartans”, e.g. Losartan)

Vasodilation

Na+ Excretion

Other antihypertensive drugs that interfere with the Renin-Angiotensin System

Other antihypertensive drugs that interfere with the Renin-Angiotensin System

ACE

KininogenAngiotensinogen

Renin Kallikrein

Angiotensin I (Inactive)

Bradykinin B2 Receptor

AT1 Receptor

Angiotensin II

Vasoconstriction

Aldosterone release

Na+ Retention

Bradykinin(1-7) (Inactive)

Blood Pressure

ReninInhibitorAliskiren

Vasodilation

Na+ Excretion