Problem+Set+3

Problem Set #3 (Dr. Sheng; PSW481) Date of submission: 11/05/2009

A. Quiz on textbook reading and prerequisite coursework. (Ali, Chau, Heinzelmann, Mathew, Patel, and Sylvestre)

(1). A diuretic with the following chemical structure can be classified as

b. High-ceiling diuretics c. Potassium-sparing d. Non of the above
 * a. Osmotic**

(2) For in vivo enzymatic metabolism, which group of compounds is more reactive? a. Alkanes
 * b. Alkenes**

(3) Briefly describe the relationship between the molecular lipophilicity and the oral bioavailability If lipophilicity is too high, oral bioavailability decreases. But a drug needs some lipophilicity so that it can cross membranes and enter tissues.

B. Discuss the pathophysiology of hypertension with your neighbors. Briefly describe it below (Almetwazi, Chen, Ho, McNeill, Patel, and Syoufjy) //Stedman's Medical Dictionary - 28th Ed:// "High blood pressure; transitory or sustained elevation of systemic arterial blood pressure to a level likely to induce cardiovascular damage or other adverse consequences. Hypertension has been arbitrarily defined as a systolic blood pressure above 140 mmHg or a diastolic blood pressure above 90 mmHg...

... An underlying disorder is identified in fewer than 10% of all cases of hypertension. The remainder, traditionally labeled "essential" hypertension, probably arise from a variety of disturbances in normal pressure-regulating mechanisms (which involve baroreceptors, autonomic influences on the rate and force of cardiac contraction and vascular tone, renal retention of salt and water, formation of angiotensin II under the influence of renin and angiotensin-converting enzyme, and other factors known and unknown), and most are probably genetically conditioned."

C. Discuss the available choices of antihypertensive drugs (Ball, Decelle, Harkins, McMahon, and Sanford) - Calcium Channel Blockers, Beta Blockers, Angiotensin Receptor Blockers, Angiotensin Converting Enzyme Inhibitors

D. List the major components of the renin-angiotensin pathway (Adebogun, Buabeng, Goldenberg, Lee, Park, and Singh) angiotensinogen, renin, angiotensin I, ACE, angiotensin II, aldosterone

E. Discuss the relationship between the renin-angiotensin pathway and bradykinin (Alsaedi, Colton, Ibrahem, Moore, Patel, and Tai ) Angiotensin Converting Enzyme (ACE) also inactivates bradykinin (a vasodilator) into inactive kinins, causing vasoconstriction, and therefore higher blood pressure.

F. Renin is b. A steroid compound c. A small molecule d. A carbohydrate
 * a. An enzyme**

G. What is the lead compound of rennin inhibitors? Discuss the history of the development of FDA-approved renin inhibitor(s) (Ameyaw, Condon, Morgan, Patel, Patel and Tashakor)

SCRIP (statine-containing renin inhibitor peptide) is the lead compound but its effect is short-lived. Changes made resulted in the production of enalkiren, which efficacious when given IV but not orally. A more lipid soluble zankiren was created. Zankiren has been removed from the market and replaced with Aliskiren, the 1st non-peptidic orally active renin inhibitor. (see gray box on pg 741, Foyes)

H. According to the textbook we are using, which drug is an FDA-approved renin inhibitor? a. Statine b. Zankiren d. A-64662
 * Aliskiren. Approved by FDA in 2007. Manufactured by Novartis:**
 * c. Aliskiren**

I. What is the lead compound of ACE inhibitors and how were ACE inhibitors developed? (Anderson, Conti, Iromuanya, Morin, Patel, and Tchani) SQ 20.881 (teprotide) ??? Originally isolated from the venom of the South American pit viper. (Foye's p. 742-744)

J. Discuss the early medicinal chemical studies resulting in the synthesis of the potent marketable ACE inhibitor captopril? For lead modification, besides proline, did scientists try other amino acids? Was there any success? (Beaulac, Dominique, Huynh, Mitsopoulos, and Skidmore)

Through studying the inhibition of carboxypeptidase A (an enzyme like ACE) by D-2 benzylsuccinic acid, researchers developed succinic acid derivatives with a C-terminal proline with the purpose of inhibiting ACE. Other amino acids were substituted for proline, but the resulting compounds were much less potent than those with proline.

K. Discuss the SAR roles of the functional groups indicated by dot-lines (Asal, Danella, Islam, Myzyri, Pereira, and Thomas)

The compound shown in this figure is the structure of the drug Enalapril. Enalapril is a prodrug for Enalaprilat. All the dotted functional groups increase the lipophillicity, therefore, oral bioavailability of the prodrug. Because the active form (enalaprilat) has very low oral bioavailabilty and the efficacy is reduced about 1000 fold when administered IV, the functional groups of the enalapril makes it a perfect candidate for a lipophillic prodrug.

L. After captopril (a sulfhydryl-containing inhibitor), why did people continue to develop dicarboxylate- and phosphonate- containing ACE inhibitors? (Asante-Somuah, Dang, Jackson, Nammour, Peters, and Tolpa)

After Captopril, there was delvelopment of dicarboxylate and phosphonate containing ACE inhibits because of the sufhydryl group on captopril. It caused adverse reactions such as skin rashes and taste disturbances. People sought out to develop compounds that lacked the sulfhydryl group in Captopril. (Foye's page 744)

M. Why all functional groups except for the first one (Lisinopril) in the R2 column in Table 28.1., Page 745, Foye’s book are -CH2CH3? How important is it in determining the pharmacokinetic properties of the drugs? Is there any significant difference between lisinopril and other compounds? (Aubin, Dauphinais, Jashari, Nayar, Potvin, and Tran) The varied ring systems seen in benazepril, moexipril, perindopril, quinapril, ramipril, spirapril and trandolapril provide enhanced binding and potency. They also lead to differences in absorption, plasma protein binding, elimination, onset of action, duration of action and dosing amount the drugs. The significant difference between lisinopril and the other compounds is that lisinopril along with catopril, are currently the only two ACE inhibitors that are not pro-drugs.