CVS MedChem

• The cardiovascular system is a key area of medicinal chemistry.
• Glyceryl trinitrate, first used in 1879, is a nitrate ester of a simple organic molecule and is volatile, readily hydrolysed and explosive.
• Isosorbide mononitrate is another nitrate ester of a simple organic molecule and is also volatile, readily hydrolysed and explosive.
• Propanolol, Metoprolol, and Bisoprolol are examples of beta-blockers, which are b-adrenergic antagonists.
• Warfarin interferes with Vitamin K and Vitamin K epoxide interconversion, has a narrow therapeutic index, many drug-drug interactions, and is affected by genetic polymorphisms.
• Trauma is an external force that damages the endothelium, exposing underlying tissue.
• Va is a co-factor for Xa, combining with it to form Prothrombinase complex.
• Anticoagulants include Vitamin K Antagonists.
• The pKa of BH is 4.50 and the pKa of HA is 3.47.
• The common pathway for thrombosis involves the extrinsic and intrinsic pathways, both initiated by thrombin release.
• Cholesterol Absorption Inhibitor: Ezetimibe
• Carvedilol is administered as the racemate and the (S)-(-)-enantiomer is both an a1 and non-selective b antagonist, while the (R)-(+)-enantiomer is a selective a1 antagonist only.
• Rapidly, extensively metabolised and excreted into the bile as the active glucuronide, thus delivered to the site of action
• Contains b -lactam ring, no antibiotic activity
• Taken alongside HMG reductase inhibitors
• Inhibits absorption of cholesterol at the brush-border in SI
• p K a (HA)
• p K a (BH + )
• Log P - 9.72
• Diltiazem and verapamil are the only representatives of each class.
• The (S)-(-)-Verapamil is most active, but undergoes more extensive first-pass metabolism than the (R)-(-)- enantiomer, so when given i.v.
• Verapamil is a Phenylalkylamine used for Angina and Hypertension.
• Tetrazole anion is 10x more lipophilic than carboxylate anion.
• Both ionized at pH 7.4, both planar.
• Calcium Channel Blockers: 1,4-Dihydropyridines, first described in 1882 by Hantzsch, are used for Hypertension.
• Sartans are AT 1 receptor antagonists that prevent vasoconstriction and aldosterone secretion, have no effect on bradykinin metabolism.
• CYP2C9 and VKORC1 are enzymes that metabolize drugs, with the S enantiomer of CYP2C9 being more potent and the R and S enantiomers of VKORC1 following different metabolic pathways.
• Oxidative metabolism of 1,4-DHPs leads to corresponding inactive pyridine.
• Ticragrelor is an ADP derivative and reversible inhibitor of the P2Y 12 purinergic receptor, with asymmetric synthesis of the intermediate cyclopropylamine moiety particularly challenging and high-yielding biocatalytic routes developed, an example of ‘green chemistry’ in action.
• The racemate prolongs the PR interval greater than the oral formulation.
• Eptifibatide and Tirofiban are antiplatelet drugs, with Eptifibatide being a cyclic heptapeptide derivative of a component of snake venom and Tirofiban being a synthetic RGD mimetic.
• Most 1,4-DHPs are symmetrical, amlodipine has additional, larger residue.
• HMG-CoA Reductase Inhibitors, also known as Statins, are used in the treatment of hypercholesterolaemia, with Simvastatin, Pravastatin, and Atorvastatin being examples.
• Rate-Limiting Calcium Channel Blockers include Diltiazem, Verapamil, and Ivabradine.
• Lovastatin and other statins with intact lactones are prodrugs, with 3,5-Dihydroxy acid being the essential, mimicking the tetrahedral intermediate produced by HMG-CoA en route to mevalonic acid.
• ACEIs are metabolised extensively in the liver, due to the larger, hydrophobic ring systems, and can also cyclise to give a diketopiperazine metabolite.
• Warfarin is a drug that inhibits blood clotting, with its in vivo activity occurring in an aqueous solution.
• Tetrazole is a bioisosteric replacement for carboxyl group.
• Anticoagulants include Direct Oral Anticoagulants (DOACs), which are not orally active and are formulated as diester prodrugs, and Atrial Fibrillation (AF) drugs, which are direct factor Xa inhibitors used in combination with warfarin in the treatment of AF.
• Angiotensin II Receptor (AT 1 ) Antagonists, known as Sartans, are particularly located in the vasculature, agonised by angiotensin II.