Slide 1ACE InhibitorsSlide 3Some Biologically Active PeptidesScheme of Peptide Hormone Processing & MetabolismStrategies for Developing Therapeutic AgentsUse of Peptides as DrugsSlide 8Slide 9Slide 10Slide 11Structure of Human Angiotensin Converting Enzyme (ACE)Slide 13Slide 14Mechanism of Action of ACE InhibitorsMechanism of Action of ACE Inhibitors IISlide 17Slide 18Clinical Use of ACE InhibitorsSide Effects/ContraindicationsSlide 21Drug InteractionsAdditional Beneficial Effects of ACE InhibitorsNovel and Unexpected Functions of ACE and ACE inhibitorsSlide 25Other antihypertensive drugs that interfere with the Renin-Angiotensin SystemRandal A. SkidgelRandal A. SkidgelACE InhibitorsFrom: Skidgel and Erdös, AHA Hypertension Primer, 2008ACE InhibitorsACE = Angiotensin I Converting Enzyme10 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 SystemsFrom: Skidgel RA and Erdös EG, Hypertension Primer, 4th Edition, Chap. A15, 2008.Some Biologically Active PeptidesACTHACTHAdrenomedullinAdrenomedullinß-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 & 22PBombesinBombesinBradykinin Bradykinin Brain Natriuretic PeptidesBrain Natriuretic PeptidesBuccalinBuccalinBursin Bursin C-Type Natriuretic Peptide C-Type Natriuretic Peptide Caerulein Caerulein Calcitonin Calcitonin Calcitonin Gene RelatedPeptideCalcitonin Gene RelatedPeptideCardiodilatinCardiodilatinCarnosineCarnosineCASH (Cortical Androgen- Stimulating CASH (Cortical Androgen- Stimulating Hormone)Hormone)CasomorphinsCasomorphinsCerebellinCerebellinCholecystokinin Cholecystokinin ChromostatinChromostatinCLIPCLIPContraceptive TetrapeptideContraceptive TetrapeptideCorticotropin Inhibiting PeptideCorticotropin Inhibiting PeptideCorticostatinCorticostatinCorticotropin ReleasingFactor Corticotropin ReleasingFactor CytokinesCytokinesDelta Sleep-Inducing PeptideDelta Sleep-Inducing PeptideDermorphin Dermorphin Dermaseptin Dermaseptin Diabetes-Associated PeptideDiabetes-Associated PeptideDiazepam 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 ErythropoietinErythropoietinFollicle Stimulating Hormone Follicle Stimulating Hormone GalaninGalaninGastric Inhibitory Polypeptide Gastric Inhibitory Polypeptide Gastrin Gastrin Gastrin-Releasing PeptideGastrin-Releasing Peptideα-Gliadorphinα-GliadorphinGranuliberin-RGranuliberin-RGlucagon Glucagon Glucagon-Like PeptideGlucagon-Like PeptideGrowth Factors Growth Factors Growth HormoneGrowth HormoneGrowth Hormone‑ ReleasingHormone Growth Hormone‑ ReleasingHormone GuanylinGuanylinInhibin Inhibin Insulin Insulin InterleukinsInterleukinsKallidin Kallidin KyotorphinKyotorphinα & ß-Lactorphinα & ß-LactorphinLeucokinins Leucokinins LipotropinLipotropinLuteinizing Hormone (LH)Luteinizing Hormone (LH)LH‑Releasing HormoneLH‑Releasing HormoneMagaininsMagaininsMastoparanMastoparanMelanin-ConcentratingMelanin-Concentrating HormoneHormoneα‑Melanocyte Stimulatingα‑Melanocyte Stimulating Hormone Hormone MelanostatinMelanostatinMorphine ModulatingMorphine Modulating NeuropeptideNeuropeptideMotilinMotilinα‑Neoendorphinα‑Neoendorphinß‑Neoendorphinß‑NeoendorphinNeurokinin ANeurokinin ANeurokinin BNeurokinin BNeuromedin NNeuromedin NNeuropeptide YNeuropeptide YNeuropeptide PNeuropeptide Pß-Neuroprotectinß-NeuroprotectinNeurotensinNeurotensinNeutrophil DefensinsNeutrophil DefensinsOrexinsOrexinsOxytocinOxytocinPACAP (Pituitary Adenylate Cyclase Activating PACAP (Pituitary Adenylate Cyclase Activating Peptide)Peptide)PancreastatinPancreastatinPancreatic PolypeptidePancreatic PolypeptideParathyroid HormoneParathyroid HormonePeptide Histidine IsoleucinePeptide Histidine IsoleucinePeptide YYPeptide YYProlactinProlactinProctolinProctolinRiginRiginSecretinSecretinSomatostatinSomatostatinSubstance PSubstance PSysteminSysteminThymosinThymosinThyrotropinThyrotropinThyrotropin ReleasingThyrotropin Releasing HormoneHormoneTuftsinTuftsinUrocortinUrocortinUroguanylinUroguanylinVasopressin (ADH)Vasopressin (ADH)VIP (Vasoactive IntestinalVIP (Vasoactive Intestinal Peptide)Peptide)ProhormonePeptidase 1RK RREndoproteaseActive PeptideProcessing EnzymeReceptor 1Receptor 2Peptidase 2 Scheme of Peptide Hormone Processing & MetabolismStrategies for Developing Therapeutic AgentsPeptidase 1Active PeptideReceptor 1Receptor 2Peptidase 2Administer the PeptideUse of Peptides as DrugsAdvantagesHighly potent/excellent specificityWide variety of Biological ActivitiesStraightforward SynthesisPredictable ChemistryLittle or no toxicity from metabolismDisadvantagesOral administration difficult because of:Degradation by digestive enzymes and intestinal peptidasesPoor absorption across tight junctions in epithelila Efflux systems may pump absorbed peptides back outInconvenient administration Rapidly cleaved by peptidasesExcreted by kidneyRelatively expensive to synthesize compared with small organic moleculesPeptidase 1Receptor 1Receptor 2Peptidase 2 Block Degradation by PeptidasesStrategies for Developing Therapeutic AgentsStrategies for Developing Therapeutic AgentsPeptidase 1Active PeptideReceptor 1Receptor 2Peptidase 2Use a Receptor AntagonistProhormonePeptidase 1RK RREndoproteaseActive PeptideProcessing EnzymeReceptor 1Receptor 2Peptidase 2Block Synthesis/ProcessingStrategies for Developing Therapeutic AgentsACEACE DISTRIBUTION Widespread, concentrated on:•Endothelial surface of the vasculature•Epithelial Brush borders•Renal proximal tubules•Small intestine•Placenta•Choroid plexusStructure of Human Angiotensin Converting Enzyme (ACE)ACEACEC-domainN-domainA given peptidase can
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