Problem+Set+3

Problem set #3

A. Based on the structure given below, please discuss the possible therapeutic applications, mechanisms of action, key structural features and the designing ideas of the medicinal chemists who developed this compound. Work #1 by LG-M1-Ackley, Bell, Faraj, Keeler, Ngang, and Sweatt Drug - Beta blocker Therapeutic applications - hypertension, Post-MI, glaucoma MoA: Antagonizes beta receptors and causes a decrease in cardiac muscle contraction via B1 blockade and peripheral smooth muscle contraction via B2 blockade. Key SAR & designing ideas : Insertion of an oxymethylene bridge (-OCH2) into an arylethanolamine structure yeilds an aryloxypropranolamine - the 1st clinically successful BB. -Side chain moved from C2 to the C1 position -In general aryloxypropranolamines are more potent than arylethanolamines

Work #2 by LG-W1-Adebogun, Buabeng, Goldenberg, Lee, Park, and Singh Therapeutic applications - Treatment of hypertension and congestive heart failure MOA - Inhibits ACE, the conversion of angiotensin I to angiotensin II. Increases bradykinin levels which in turn, stimulate prostaglandin biosynthesis. Key SAR - Tripeptide substrates:Negative charged carboxylate, Zn binding, R1 & R2 side chains gives overall binding affinity, does not have hydrophobic pocket, and N terminal peptide bond for H-bonding between substrate and ACE. Designing ideas - Lead compound SQ20881 had its limitation because it is a peptide drug and cannot be administered orally. And with further research, ACE has properties similar to pancreatic carboxypeptidases, carboxypepidase A. Negative charge at C-terminal binds to positively charged Arg on enzyme. Hydrophobic pocket for C-terminal. And zinc atom located labile peptide bond serves to stabilize negatively charged tetrahedral intermediate.

B. Case Study (Foye’s) “VD is an 81-year-old, white, female housewife with rheumatoid arthritis (RA). Her RA is treated with low-dose methotrexate (10 mg/week) and celecoxib (100 mg b.i.d.). She manages to cook but her cantankerous 77-year-old husband does the housework and shopping. VD also suffers from type 2 diabetes, and her plasma glucose is well maintained with glipizide. VD visits her physician every 3 months, and during her last visit her cholesterol was elevated (250 mg/dL) so therapy with simvastatin (20 mg/day at bedtime) was initiated. VD has always had normal blood pressure, but during her most recent examination her pressure was 150/95 mm Hg, which persisted over the next 3 days. VD already maintains a healthy diet in controlling her type 2 diabetes, but her RA and age precludes strenuous exercise.”

1. Please fill out the blank areas with appropriate key words a. Compounds a and b Work #1 by LG-M2-Adabie, Bou-Mitri, Finke, Kibazo, O'Connor, and Taylor Compound a: methyldopa, an alpha-2 adrenergic agonist MOA - Central conversion to alpha-methylnorepinephrine, which is stored in adrenergic vesicles and replaces NE. Alpha-methylnorepinephrine then activates alpha-2 receptors, thus blocking the final common pathway for sympathetic outflow to the peripheral organs. Key Structural Features - Catechol structure allows for metabolism by MAO and COMT once methyldopa is decarboxylated.

Compound b: diazoxide, nondiuretic potassium channel opener __MOA__: reduces peripheral vascular resistance and blood pressure by a direct vasodilating effect on the vascular smooth muscle by activating the ATP-modulated potassium channel; this prolongs the channel opening allowing greater vasodilation on arterioles (also increases blood glucose through inhibition of pancreatic insulin secretion, stimulation of catecholamines and increase of hepatic glucose release) __Key Structures__: structurally similar to thiazide diuretics but with no diuretic action due to the removal of sulfonamide – has a benzothiadiazine 1,1-dioxide core structure, Chloro substitute at carbon 7 increases the activity, methyl group at carbon 3 increases lipophilicity and potency

Work #2 by LG-W2-Afolayan, Cabral, Goodrich, Lee, Patel, and Snell

MOA: The exact mechanism of antihypertensive action has not been conclusively demonstrated. However, the major antihypertensive effect appears to result from conversion to alpha-methylnorepinephrine, a potent alpha-2 adrenergic agonist. Alpha-methylnorepinephrine acts centrally to stimulate alpha receptors. This results in a decrease in sympathetic outflow and decreased blood pressure
 * Methyldopa -** alpha-2 adrenergic agonist

MOA:
 * Diazoxide-** nondiuretic potassium channel opener
 * Oral-Systemic: Hyperglycemic effect is due primarily to inhibition of insulin release from the pancreas, as well as an extrapancreatic (catecholamine-induced) effect.
 * Parenteral-Systemic: Exact mechanism of antihypertensive action is unknown. Diazoxide produces arteriolar vasodilation and decreased peripheral resistance.
 * Diazoxide has a hyperglycemic effect that is due primarily to inhibition of insulin release from the pancreas, as well as an extrapancreatic (catecholamine-induced) effect.

b. Compounds c and d Work #1 by LG-M3: Addo, Bui, Finneran, Kothari, Pang, and Urbach Compound c: Clonidine Compound d: Verapamil Work #2 by LG-W3: Afrane, Cardoso, Gossiho, Libera, Patel, and Sok Compound C: Clonidine MOA: Clonidine has both alpha1 agonist activites causing vasoconstriction as well as alpha2 adrenergic activity that will decrease sympathetic output once it crosses the blood brain barrier. Key structural features: Clonidine has 2 lipophilic ortho-dichloro substituents on the phenol ring that can be substituted by methyl groups and not lost any potency or selectivity. The uncharged form exists as a pair of tautomers. Compound D: Verapamil MOA: Verapamil works by inhibiting the L-type voltage-dependent calcium channels of the heart which will in turn prevent depolarization of the SA node. It also has some vasodilation effect on vascular smooth muscles. Key structural features: The S enantiomer is more potent. The compound contains a tertiary amine that is ionized at physiological pH and causes the drug to bind to a different binding site than the dihydropyridines. 2. What are the diagnoses for this patient? The patient’s physician plans to initiate antihypertensive therapy and has the above drugs available for this patient. Please evaluate each drug in relation to this case and make a recommendation to the physician and provide your counseling tips to the patient. LG-M4. Alhammad, Caron, Fletcher, Lalinde, Piehler, and Valder The patient's blood pressure is classified as stage I hypertension. The patient also has a compelling indication with DM-2. According to JNC-7 guidelines, the only agent that can be used from the listed drugs above is verapamil. Other agents could be associated with some side effects that may interfere with patient's blood pressure control. LG-W4-Akwari, Caron, Guan, Liu, Patel, and Stevenson. The patient has stage I hypertension. Because of her diabetes, the preferred agent out of the choices here would be the verapamil, because of its indication for diabetes. All of the agents above interact with the Celecoxib, an NSAID, and we would have to be very careful to monitor the patient for blood pressure and edema. Clonidine would not be a good choice in this instance because it can mask the signs of hypoglycemia and interact with the effects of the patient’s glipizide.
 * MOA:
 * Centrally active sympatholytic; stimulation of a2-adrenoceptors causing inhibition of sympathetic output, leading to reduced peripheral and renovascular resistance that leads to decrease in systolic and diastolic blood pressure.
 * Key structural features in determining therapeutic effect, potency, and/or pharmaceutical properties:
 * Imidazole ring increases potency.
 * MOA:
 * Inhibits calcium ion influx into myocardial cells.
 * Produce negative inotropic effect by interrupting contractile response of calcium and troponin.
 * Inhibit vascular smooth muscle contraction by depriving the cell from calcium ions, so cannot cause constriction by binding to specific intracellular protein calmodulin to form a complex that initiates the process of vascular constriction.
 * Key structural features in determining therapeutic effect, potency, and/or pharmaceutical properties:
 * Structurally characterized by central basic nitrogen to which alkyl and aralkyl groups are attached.
 * Both chiral, possessing asymmetric centers; (+) is approximately one order of magnitude more potent than (-) enantiomer.