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Cellular communications present in cardiovascular system In this system are involved many biological substances of different therapeutic importance and relevance with different signal transductions Blood Pressure Regulation Sympathetic nervous control Blood Pressure Regulation Involvement of RAS system Drugs affecting the cardiovascular apparatus Most prescribed classes of antihypertensive drugs (US) Beta blockers and ACE inhibitors account for 58% of all antihypertensives prescribed in the US. Antihypertensive drugs ACE inhibitors, indications include heart failure, left ventricular dysfunction and diabetic nephropathy; contra-indications include renovascular disease and pregnancy; Angiotensin-II receptor antagonists are alternatives for those who can not tolerate ACE inhibitors because of persistent dry cough, but they have the same contra-indications as ACE inhibitors. Beta-blockers, indications include myocardial infarction, angina; compelling contra-indications include asthma, heart block; Calcium-channel blockers: are valuable in isolated systolic hypertension in the elderly when a low-dose thiazide is contra-indicated or not tolerated. Alpha-blockers, a possible indication is prostatism; a contra-indication is urinary incontinence; Diuretics, particularly indicated for hypertension in the elderly; a contra-indication is gout; Drugs affecting the renin-angiotensin system (RAS) 1. 2. 3. Renin inhibitors, Angiotensin-converting enzyme inhibitors Angiotensin-II receptor antagonists Therapeutic application for: HYPERTENSION ACE inhibitors should be considered for hypertension when thiazides and beta-blockers are contra-indicated, not tolerated, or fail to control blood pressure. HEART FAILURE ACE inhibitors have a valuable role in all grades of heart failure, usually combined with a diuretic. MYOCARDIAL INFARCTION ACE inhibitors are used in the immediate and long-term management of patients who have had a myocardial infarction. Angiotensin-II receptor antagonists, although not licensed for heart failure, may be useful alternatives for patients who, because of symptoms such as cough, cannot tolerate ACE inhibitors. Renin-Angiotensin System vasopressin La secrezione di renina renina La è un enzima proteolitico che viene secreto nel circolo ematico delle cellule dell’apparato iuxtaglomerulare, un agglomerato di cellule di origine muscolare, che rivestono le arteriole afferenti determinandone la pressione interna. Gli stimoli per la liberazione di renina sono: a)di origine neuronale, neuroni simpatici b-1, b)quantità di liquido che passa nelle arteriole (pressione di perfusione renale) c)concentrazione di ioni sodio nei fluidi presenti nel tubulo distale al quale è esposta la macula densa. (Le cellule della macula densa sono in grado di sintetizzare prostanoidi che danno un segnale positivo di secrezione alla juxtaglomerulare e negativo con la secrezione di adenosina). Comunicazione paracrina per la sintesi di renina Corpuscolo renale L'apparato juxtaglomerulare è indicato dalla lettera D e comprende: 5b. Mesangio – cellule extraglomerulari 6. Cellule granulari (cellule juxtaglomerulari) 7. Macula densa RENIN-ANGIOTENSIN CASCADE Angiotensinogen is the precursor molecule, and it is produced mainly in the liver, (although other sites have been thought to contribute to local effects of the molecule). In humans, the peptide sequence for angiotensinogen (485 amino acids long) which contains (immediatly after the signal peptide) the 10 aa: H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Xaa-XbbRenin acts to cleave the peptide bond between the leucine (Leu) and the valine (Val) residues. The ten amino acid peptide (bold) angiotensin I is created. Angiotensinogen Angiotensinogen is an -2-globulin, a group of globular proteins in plasma, that is produced constitutively and released into the circulation mainly by the liver. It is a member of the SERPIN family, a group of proteins with similar structures that were first identified as a “set of proteins” able to inhibit proteases, (the acronym serpin was originally coined because many serpins inhibit chymotrypsin-like enzymes, serine protease inhibitors), although it is not known to inhibit other enzymes, unlike most serpins. Plasma angiotensinogen levels are increased by plasma corticosteroid, estrogen, thyroid hormone, and angiotensin II levels. Angiotensinogen is also known as renin substrate. Human angiotensinogen is 452 amino acids long, but other species have angiotensinogen of varying sizes. The first 12 amino acids are the most important for activity. ACE processing The decapeptide angiotensin I (AI) is cleaved into the octapeptide angiotensin II (AII) by angiotensin-converting enzyme (ACE). Angiotensin-converting enzyme (ACE) has a critical role in cardiovascular function by cleaving the carboxy terminal His-Leu dipeptide from angiotensin I to produce a potent vasopressor Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu octapeptide, angiotensin II. + H-L Localizzazione dell’ ACE L’ACE è un enzima di membrana posto sulla superficie delle cellule endoteliali, ed è particolarmente abbondante nei polmoni dove è presente una superficie di endotelio vascolare molto grande. La proteina enzimatica è presente anche in altri tessuti vascolari del cuore, del SNC, nel muscolo striato e la sua localizzazione non sembra limitata al solo endotelio. The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. ACE cleaves also Bradykinin peptides Inhibitors of ACE are a first line of therapy for hypertension, heart failure, myocardial infarction and diabetic nephropathy. Notably, these inhibitors were developed without knowledge of the structure of human ACE, but were instead designed on the basis of an assumed mechanistic homology with Carboxypeptidase A. The peptidase reaction R H N O A peptide substrate R' Enzyme + H2O R OH O H2N R' RENIN is an Aspartyl Proteases, a sub-subclass of ENDOPEPTIDASES that depend on an ASPARTIC ACID residue for their activity. EC 3.4.23. Mammalian Renin H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Xaa-Xbb- Design of renin inhibitors pseudopeptide amino component The time neded to develop renin inhibitor to use in therapy Tekturna: the first renin inhibitor Tekturna (Aliskiren) was approved by the FDA in March 2007 and it is the first renin inhibitor and the first member of a new class of antihypertensive drugs in a decade. The drug inhibits the activity of renin, leading to a decrease in angiotensin I and a subsequent reduction in angiotensin II. Specific inhibitors of renin reduce Ang II generation, but unlike ACE-inhibitors they do not cumulate other peptides like Substance P or Bradykinin and consequently untoward drug effects like: cough and angioedema are not to be expected. Several specific renin inhibitors were synthesized as of the 1970s, but low efficacy or the lack of oral availability or high cost of synthesis always prevented renin inhibitors from becoming successful drugs. OH H2N * H N * * * O NH2 O O O O COOH HOOC 2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy-)phenyl]octanamid hemifumarate Design of ACE inhibitors Knowledge of the similar enzyme Carboxypeptidase A A mechanism of Carboxypeptidase A Carboxypeptidase A is a digestive enzyme that hydrolyzes the carboxyl-terminal peptide bond in polypeptide chains. The enzyme serves as a good illustration of protein secondary structure. The single polypeptide chain of 307 amino acids contains regions of alpha helix (385) and beta pleated sheet (17%). Hydrolysis occurs most readily if the carboxyl-terminal residue has an aromatic or a bulky aliphatic side chain Catalitic mechanism of CPA Binding of a typical substrate such as glycyl-tyrosine results in a structural rearrangement of the active site (induced fit). Residues which are thought to interact with the substrate include Glutamate 270, Arginine 145, Arginine 127, and Tyrosine 248. A zinc atom is coordinated in a tetrahedral array with the amino acids Histidine 69, Histidine 196, and Glutamate 72, and either a water or substate molecule. The zinc atom is a prosthetic group that is essential for enzymatic activity and is largely responsible for the electronic strain created at the active site. In the illustration below, zinc polarizes the carbonyl group of the peptide bond in glycyl-tyrosine, making it more susceptible to attack by Glutamate 270. Subtrate and inhibitor of CPA Requirements of CPA and ACE for the development of enzyme inhibitors OH O EDITPEP OH N H O O CPA inhibitor CPA substrate HN HN N N O EDITPEP OH R N H H N O H N R OH O OH O O ACE substrate H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-OH ACE inhibitor ? Interaction of ACE with a substrate Angiotensin I Phe His Leu-OH Glu H2O Angiotensin I is a substrate of ACE Arg His His His Design of ACE inhibitors considering the knowledge of CPA inhibitors O H N O R N H R' O HS R' OH O R N H OH O Teprotide, is a Bradykinin-Potentiating Peptide Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro-OH In the 1960 it was observed that the venom of the Brazilian pit viper Bothrops jararaca, contains peptides capable of intensifying responses to bradykinin. The venomous peptides tourned out to be inhibitors of kininase II, a bradikynin-inactivating enzyme, which subsequently was shown to be identical with ACE. Based on the sequence of one of the key venomous peptides, the peptide teprotide was synthesized and shown also to be an inhibitor of ACE. The presence of Pro residues and an N-terminal Pyroglutammic acid, made the teprotide relatively resistant to proteolytic decomposition in vivo, but it was not sufficiently stable for oral administration. Teprotide became the primary lead struucture in a drug design project aiming at the development of the low-molecular weight analogues showing potent ACE inhibition activity and desirable pharmacokinetic properties. Two structural features were considerd essential for activity, namely the presence of a C-terminal Pro residue and a functional group capable of co-ordinating effectively with the zinc atom in the enzyme. As a result of the sistematic reduction of the moleculat weight of teprotide following this strategy and by using bovin carboxypeptidase A as the assay enzyme, N-succinyl-Pro was synthesized and shown to be a mederately potent ACE inhibitor. HN N O HO O COOH N H N R O O OH Ace Inhibitors in therapy captopril - Capoten by Bristol-Myers Squibb enalapril - Vasotec by Merck benazepril - Lotensin by Novartis lisinopril - Prinivil by Merck or Zestril by Astra-Zeneca quinapril - Accupril by Pfizer ramipril - Altace by Hoechst Marion Roussel, King Pharmaceuticals moexipril/spirapril - Univasc by Schwarz Pharma trandolapril - Mavik by Knoll Pharmaceutical (BASF) perindopril erbumine - Aceon by Rhone-Polenc Rorer imidapril - Not approved for human use in the USA - approved in Japan fosinopril - Monopril by Bristol-Myers Squibb O HS COOH N Captopril (S)-1-(3-Mercapto-2-methyl-1-oxopropyl)-L-proline Chemical approach to captopril analogues HN N O EDITPEP N H O HO O H N O COOH N O ACE substrate OH O O HO O HS COOH N COOH N Captopril modify distance O HO O H N COOH N R New analogues O H N O O HO R OH N H R' O O H N Design of ENALAPRIL COOH H N N R Enalapril H3 C-H 2C-OOC O COOH N (S)-1-[N2-[(1-Etossicarbonyl)-3-phenylpropyl-]-L-alanyl-]-L-proline H N HOOC O COOH N (S)-1-[N-(1-Carboxy-3-phenylpropyl-)-L-alanyl-]-L-proline Design of ENALAPRIL analogues with modifications at the Alanine or Proline residue H N HOOC Lisinopril O COOH N H N H3 C-H 2C-OOC H2N (S)-1-[N2-[(1-Carboxy)-3-phenylpropyl-]-L-lysyl-]-L-proline O COOH N Quinapril H N H N H3 C-H 2C-OOC O COOH H3 C-H 2C-OOC O COOH N N (S)-2-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl-]-amino-]-1-oxopropyl]-1,2,3,4-tetrahydroisoquinolin-3-carboxylic acid COOH COOH H2N COOH HN HN COOH HN Pipecolic acid Phe Tic, a constrained analog of Phe an analog of Pro H N O N H3 C-H 2C-OOC H N H3 C-H 2C-OOC O H COOH COOH COOH N HN H COOH HN H H Ramipril (S)-1-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl]-amino]-1-oxopropil]-octaidrociclopenta-[b]-pirrolo-2-carboxylic acid H N Trandolapril H3 C-H 2C-OOC H N H3 C-H 2C-OOC O H COOH O COOH N Enalapril N H (S)-1-[2-[[1-(Ethoxycarbonyl)-3-phenylpropyl-]-amino-]-oxopropil]-octaidro-1H-indolo-2-carboxylic acid H N O N H3 C-H 2C-OOC H N H3 C-H 2C-OOC O COOH COOH Spirapril N S S COOH HN (8S)-7-(2S)-[2-[[(1S)-1(-etoxycarbonyl)-3-phenylpropyl]-amino]-1-oxopropyl]1,4-dithia-7-azaspiro[4,4]nonan-8-carboxylic acid COOH HN S S H N H3 C-H 2C-OOC H N H3 C-H 2C-OOC O O COOH N COOH N COOH HN COOH HN N-alkyGly Delapril (S)-N1-(2,3-Dihydro-1H-inden-2-yl)-N1-[N2-(1-ethoxycarbonyl)-3-phenylpropyl-]L-alanil-]-glicine Design of ENALAPRIL analogues with modifications at the Ala and Pro residues O H N COOH H N O H3 C-H 2C-OOC COOH N N N H3 C-H 2C-OOC Cilazapril [S-[1a, 9a ]-9-[1-(etossicarbonil)3-fenilpropil]-amino]-octaidro-10-oxo-6H-piridazino-[1,2a][1,2]-diazepin-1-carbossilico acido COOH H2N COOH H2N COOH COOH Glu COOH HN HN Piperazic acid HN H N H3 C-H 2C-OOC O H N COOH N H3 C-H 2C-OOC Quinapril O COOH N O H N COOH N H3 C-H 2C-OOC Delapril H N O COOH N N H3 C-H 2C-OOC Cilazapril H N H3 C-H 2C-OOC O COOH N H2N O COOH N H2N O N N Benazepril (3S)3-[[(1S) 1-(etossicarbonil)-3-fenilpropil]-amino]-2,3,4,5-tetraidro-2-oxo-1H-1-benzazepin-1-acetico acido COOH Design of ENALAPRIL analogues with modifications in different points of the molecule O H N N H3 C-H 2C-OOC General structure of these derivatives R2 p X R3 O O R 1 O COOH COOH N R O HS COOH N X = C H2 , O, NH, or ab sent O P O O COOH N O X is absent, R1 is H, R2 is an alkyl group and R3 is an ether/ester function O Fosinopril (4S) 4-Cyclohexyl-1-[[[2-methyl-1(1-oxopropoxy)-propoxy]-(4-phenybuthyl)-phosphinyl]-acetyl]-L-proline Zofenopril calcium chemically known as (4S)-l-[(2S)-3-(benzoylthio)-2-methylpropionyl]-4- (phenylthio)-L-proline calcium salt Zofenopril is a non-peptidic orally active sulphydryl ACE inhibitor with long lasting action, which is approved for the treatment of hypertension. It is a further modification of the CAPTOPRIL, the first ACE inhibitor Angiotensin-II receptor antagonists Candesartan, irbesartan, losartan, and valsartan are specific angiotensin-II receptor antagonists with many properties similar to those of the ACE inhibitors. Eprosartan, olmesartan, and telmisartan have been introduced more recently. However, unlike ACE inhibitors, they do not inhibit the breakdown of bradykinin and other kinins, and thus do not appear to cause the persistent dry cough which commonly complicates ACE inhibitor therapy. This panel shows the Angiotensin II and AT1 receptor in cartoon mode, with some of the loops connecting the helices omitted for clarity. This 3D-structure is a model based on the rhodopsin receptor to guide folding of the AT1-receptor sequence. H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-OH Angiotensin II receptor, type 1 Angiotensin II receptor, type 1 or AT1 receptor is an angiotensin receptor. It has vasopressor effects and regulates aldosterone secretion. It is an important effector controlling blood pressure and volume in the cardiovascular system. Angiotensin II receptor antagonists are drugs indicated for hypertension, diabetic nephropathy and congestive heart failure The angiotensin receptor is activated by the vasoconstricting peptide angiotensin II. The activated receptor in turn couples to Gq/11 and thus activates Phospholipase C and increases the cytosolic Ca2+ concentrations, which in turn triggers cellular responses such as stimulation of protein kinase C. Activated receptor also inhibits adenylate cyclase and activates various tyrosine kinases. Angiotensin II receptor, type 2 AT2 belongs to a family 1 of G protein-coupled receptors, it is an integral membrane protein that plays a role in the central nervous system and cardiovascular functions that are mediated by the renin-angiotensin system. This receptor mediates programmed cell death (apoptosis). In adults, it is highly expressed in myometrium with lower levels in adrenal gland and fallopian tube. Stimulation of AT2 by the selective agonist increases mucosal nitric oxide production Amino acid residues of AII involved in receptor interaction H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-OH Binding of Angiotensin II to the AT1 receptor, looking down on the receptor from the top, circles represent transmembrane helicies . Some transmembrane helicies have been omitted for clarity. The N-terminal region of angiotensin is represented by R for simplicity. The D(Asp 281) N(Asn 111) K(Lys 199) H(His 256) binding sequence is shown in RED, other amino acids that are peripherally related in stabilizing the molecule are shown in BLACK. Drugs act by mimicking the structure of the natural neurotransmittesr and hormones. There may be an almost direct structural correspondence between the drug and hormone (e.g. saralasin/angiotensin) or the structures may be superficially quite different (e.g. losartan), but the drugs shape and electrostatic charge distribution mimics the shape and charge of the natural compound. Whether a drug is an agonist or antagonist depends on a number of structural issues. H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-OH, angiotensin II agonist H-Sar-Arg-Val-Tyr-Val-His-Pro-Ala-OH, SARALASIN antagonist Design of Losartan H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-OH, angiotensin II Cl N Cl COOH N COOH N N R R R = Cl, NO 2, CH3, OH, OCH 3 X X = s pace r, CH2, O, CO-NH, CH=CH, etc. Design of Losartan Losartan Cl N Cl OH N COOH N N N N N N H R R = COOH or other groups 2-Butyl-4-chloro-1 {[2'-(1H-tetrazol-5-yl)-1,1’-biphenyl-4-yl]methyl}-1H-imidazol-5-methanol Cl N OH N Design of LOSARTAN analogues N N N N H N O N COOH N O O N O N N N N H candesartan O O O N N N N H Candesartan cilexetil 2-etossi-1-[[2'-(1H-tetrazol-5-il)[1,1'-bifenil]-4-il]-metil]-1H-benzimidazolo-7-carbossilico acido Cl N OH N N N irbesartan O N N N N H 2-butil-3-[[2'-(1H-tetrazol-5-il)-1,1'-bifenil-4-il]-metil]-1,3-diazaspiro[4.4]non-1-en-4-one N N N N H Cl N O OH N N COOH N N N N H valsartan N-(1-oxopentil)-N-[[2'-(1H-tetrazol-5-il)-1,1'-bifenil-4-il]-metil]-L-valina N N N N H Fine presentazione L'adenoipofisi secerne sei importanti ormoni: il GH (Ormone della Crescita o Somatotropina), che regola la crescita ed il metabolismo intermedio; la PRL (Prolattina), essenziale per la produzione del latte durante la gravidanza ed il puerperio; l'LH (Ormone Luteinizzante) e l'FSH (Ormone Follicolo Stimolante), che controllano le funzioni gonadiche nell'uomo e nella donna; il TSH (Ormone Tiroido Stimolante o Tireotropina), che regola la funzione della tiroide; l'ACTH (Ormone Adrenocorticotropo) che, regolando le funzioni della corteccia delle ghiandole surrenali, influenza i livelli di cortisolo circolanti. La neuroipofisi svolge la sua funzione agendo da "serbatoio" per due ormoni prodotti dai neuroni dell'ipotalamo: la Vasopressina (AVP o Ormone Antidiuretico), che controlla l'equilibrio idrico dell'organismo agendo sul rene; l'Ossitocina ha, invece, importanza nel regolare la lattazione ed i fenomeni del parto.omeni del parto. Comparison of binding of angiotensin (left hand panel) and the antagonist Losartan (Right hand panel) to the AT1 receptor This is a molecular model of the unbound carboxypeptidase A enzyme. The cpk, or space-filled, representation of atoms is used here to show the approximate volume and shape of the active site. Note the zinc ion (magenta) in the pocket of the active site. Three amino acids located near the active site (Arg 145, Tyr 248, and Glu 270) are labeled. This is a cpk representation of carboxypeptidase A with a substrate (turquoise) bound in the active site. The active site is in the induced conformation. The same three amino acids (Arg 145, Tyr 248, and Glu 270) are labeled to demonstrate the shape change. Tekturna: the new kid on the block • Novartis's Tekturna (aliskiren) was approved by the FDA in March 2007 and is the first renin inhibitor and the first member of a new class of antihypertensive drugs in a decade. The drug inhibits the activity of renin, leading to a decrease in angiotensin I and a subsequent reduction in angiotensin II. Late-stage trials with Tekturna used as monotherapy (75–600 mg daily), showed a significant decline in blood pressure compared with placebo. • Specific inhibitors of renin reduce Ang II generation, but unlike ACE-inhibitors they do not cumulate other peptides like substance P or bradykinin and consequently untoward drug effects like cough and angioedema are not to be expected. • Several specific renin inhibitors were synthesized as of the 1970s, but low efficacy or the lack of oral availability or high cost of synthesis always prevented renin inhibitors from becoming successful drugs. H N H3 C-H 2C-OOC Imidapril O COOH N O N (4S)-3-[(2S)-2[[1-(Ethoxycarbonyl)-3-phenylpropyl]-amino]-1-oxopropyl]-1-methyl-2-oxo-imidazolidine -4-carboxylic acid 2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy-)phenyl]octanamid hemifumarate Most prescribed classes of antihypertensive drugs (US) Beta blockers and ACE inhibitors account for 58% of all antihypertensives prescribed in the US.