□ Antihypertensives Tomáš Goněc 21.11.2011 Hypertension B □ blood pressure > 135/85 mmHg □ most common cardiovascular disease □ untreated = major risk of coronary artery disease, heart failure, stroke, renal failure □ long-time untreated hypertension: left ventricule hyperthropy, retinopathy, angina pectoris, lung, liver, renal failure Hypertension - drug therapy □ central and peripheral autonomic inervation □ blood vessel wall relaxation □ renine-angiotensine-aldosteron system □ diuretics □ other mechanism a2-adrenergic and imidazoline receptor agonists ci nh UC1 H A-Vynh' 1^ac| o nh Clonidine Guanabenz Guanfacine och3 h ^\ nNHCH(CH3)2 ArC^X^NHCHtCHaJa R absolute configuration S absolute configuration Fig. 11.18. Stereochemical nomenclature for arylethanolamines versus aryloxypropanolamines. The relative positions in space of the four functional groups are the same in the two structures; however one is designated (R) and the other (£). This is because the introduction of an oxygen atom into the side chain of the aryloxypropanolamine changes the priority of two of the groups used in the nomenclature assignment. 11 ß-blockers - non selective ch3 oh " ch3 o Bunolol Levobunolol, S(-) isomer Nadolol ch3 i I. h • oh ch3 ch3 oh n ch3 o n Carteolol ch3 h 'ohh 6h3 (S)-Penbutolol ch3 o-^n^ch. ch3vA. oh ch3-^f^"ch3 o___.ch3 T o Metipranolol ch3 X oh Pindolol oh h ch3so2nh ch3 ch3 Sotalol ch3 o-^Y^N^CH3 1 oh h Propranolol Fig. 11.15. Non-selective (^adrenergic antagonists. oh ch3 n^n ch3 (S)-Timolol 3-blockers - cardioselective CH3 'oh CH3 O Acebutolol CH3 OH O Esmolol CH3 OH " O Atenolol CH3 0-Y^NACH3 OH " °^CH3 Metoprolol CH3 _ 1 O^r^N^CHa OH H Betaxolol CH3 OH CH, Bisoprolol Fig. 11.16. Selective ß.-adrenergic antagonists. Mixed ß + a antagonists B Labetalol Carvedilol Fig. 11.17. Mixed oc/ß-adrenergic antagonists. Ca2+blockers Fig. 23.20. Cellular mechanisms for the influx, efflux, and sequestering of Ca2\ Key: ROC = receptor-operated Ca2+ channels; PDC = potential-dependent Ca2" channels; SR = sarcoplasmic reticulum, M = mitochondria. Ca2+blockers a □ Verapamil, diltiazem □ dihydropyridines General structure: Rt 6 N ' CH3 IT R2 4 3^3 H (CH3)2CH02C' Isradipine: Compounds R, R2 R3 X Amlodipine CH2OCH2CH2NH2 C02CH2CH3 C02CH3 2-CI Felodipine CH3 C02CH2CH3 C02CH3 2,3-Cla Nicardipine CH3 C02CH2CH2-NH-CH2-C6H5 C02CH3 3-N02 CH3 CH3 Nifedipine CH3 C02CH3 C02CH3 2-N02 Nimodipine CH3 C02CH2CH2OCH3 C02CH(CH3)2 3-N02 Nisoldipine CH3 C02CH2CH(CH3)2 C02CH3 2-N02 Asp-Arg-Val—Tyr—lle-His-Pro-Phe—HisfLeu-Val|-lle-R RAA system □ Angiotensinogen Renin Asp-Arg-Val—Tyr—lie-His-Pro4Phe—His Heu Angiotensin I Angiotensin Converting Enzyme Asp-Arg-Val—Tyr—lle-His-Pro-Phe Angiotensin II Aminopeptidase Arg-Val—Tyr—lle-His-Pro-Phe Angiotensin III Endo- and Exopeptidase Inactive Peptides Prolyl-endopeptidase Asp-Arg-Val—Tyr—lle-His-Pro -* Angiotensin 1-7 ACE inhibitors - mechanism of action ace Fig. 23.10. A modified model of ACE inhibitor binding. L General Structure: <\^-0Rs ACE Compounds □ Lisinopril Moexipril RING Ring —N^) H02C C02H OCH3 Benazepril Q^O^Hs (CH,)4NH2 CH, 0 CHjCOOH CHjCHs Perindopril Quinapril H, H02C -r9 H02C CH, CH, CH2CH3 CH2CH3 CH, Ramipril H\f)—("HH CH3 ch2ch, Spirapril Trandolapril H02C H02C Hli'J—HH H02C CH, CH3 CH2CH3 CH5CH3 0 ACE inhibitors □ Angiotensin II inhibitors □ Mimics the C-terminal N \iviiirnu£> Li it; v^~cl carboxylic acid co2h Mimics Tyr Provide a better mimic of Phee co£h Add carboxylate S-8308 co2h Eprosartan Angiotensin II inhibitors Losartan (IC50 = 0.019|iM) Valsartan a O CH3 O Irbesartan in vivo CH, H02C Telmtsartan Candesartan cilexetil Candesartan