HTN Med Chem

Question 1

the potency of a diuretic is related to ____

Answer 1

where in the renal system the diuretic acts and how much Na is reabsorbed in those location

Question 2

~25% of Na is reabsorbed in the ___

Answer 2

loop of henle (why loop diuretics are the most potent)

Question 3

K sparing diuretics act where __% of Na is reabsorbed

Answer 3

1-2

Question 4

thiazide diuretics act in a location where __% of Na is reabsorbed

Answer 4

5

Question 5

t/f they are not completely sure how thiazides bind

Answer 5

t

Question 6

thiazide are weakly ___ (acidic/basic) due to what functional groups?

Answer 6

acidis; 2 sulphonamide acids

Question 7

what are the structural differences between HCTZ and thiazide-like diuretics?

Answer 7

thiazide-like have the same sulphonamide on the left side, but the stronger sulphonamide on the middle ring is removed, this makes the thiazide-like diuretics less acidic

Question 8

what are the key features of loop diuretics?

Answer 8

have the same aromatic ring, electron withdrawing, sulphonamide structure as HCTZ but have a very strong carb acid

Question 9

are K sparing diuretics acidic or basic? What parts of the structure show this?

Answer 9

basic, the amino groups

Question 10

aldosterone antagonists have a ___ backbone

Answer 10

steroid

Question 11

spironolactone is similar enough to ___ that it can have ADRs. What are these ADRs?

Answer 11

testosterone; androgenic (rare)

Question 12

eplenerone has fewer androgenic ADRs, than spironolactone, why?

Answer 12

structural changes

Question 13

how were RAAS drug developed?

Answer 13

in a rational logical way

Question 14

when using ACE-I, there can be a build-up of ___as a side effect of inhibiting the RAAS

Answer 14

bradykinon

Question 15

ACE was the first enzyme of the RAAS to be targeted, and what environmental substance was found to inhibit>

Answer 15

snake venom

Question 16

what amino acids of angiotensin 1 do ACE likely bind to?

Answer 16

Phe and His

Question 17

ACE carboxyl peptidases look for a ____ at the endof amino acid because an inmportant part of the active site of ACE has a ___ that seeks a negative charge

Answer 17

carb acid; arginine

Question 18

ACE active site has a __ion that helps hold things in the active site

Answer 18

zinc

Question 19

binding between angiotensin 1 and ACE

Answer 19

carbonyl on phenylalanine binds with zinc, carb acid binds to arginine on ACE. The amide bind between Phe and His is broken

Question 20

binding between 2-benzyl succinic acid and ACE

Answer 20

carb acid binds to arginine, carbonyl binds to zinc

Question 21

how does2- benzyl succinc acid inhibit ACE?

Answer 21

binds but does not have a amide bond to break, so it just sits in there and blocks activity

Question 22

how was 2-benzyl succinic acid turned into captopril and why does this improve activity?

Answer 22

addition of proline-like structure, the ACE enzyme doesnt like proline. Also changed the carb acid that binds to zinc to a sulpher hydro group which binds to zinc must stronger

Question 23

what are some disadvantages of the sulfur in captopril?

Answer 23

leaves a bad taste in the mouth and it may bind to the cysteine in foods

Question 24

how was enalapril made?

Answer 24

took captopril and replaced with a phenethyl ring that is present on angiotensin 1

Question 25

why are ACE-I taken as coxyl-esterase prodrugs?

Answer 25

carb acids are needed for binding, but they do not allow good biovailability, so given as prodrugs to improve this

Question 26

what are the 4 important parts of the SAR of ACE-Is?

Answer 26

1. N ring must contain a carb acid to mimic the C terminal carboxylate of ACE substrates
2. large hydrophobic heterocylic rings (N ring) increase potency
3. sulfhydro group is most potent and other groups must have a phenethyl group added to compensate
4. esterification of carboxylate or phosphinate increases oral F

Question 27

what are the 3 main SAR features of angiotensin 2 that need to be there for ARB development?

Answer 27

1. wacky carbon thing
2. 2N ring
3. carb acid on far right

Question 28

when developing ARBs, they thought he carb acid may have been limiting PO F, so they changed the acid to ____

Answer 28

tetrazole (resonance made H more acidic)

Question 29

what is the only renin inhibitor?

Answer 29

aliskerin

Question 30

what are the 3 types of CCBs?

Answer 30

diltizem, verapamil, 1-4 DHP

Question 31

what is the structure of Alisriken trying to mimic?

Answer 31

the transition state of angiotensinogen

Question 32

what part of alisriken mimics the amide bond being broken by the renin enzyme?

Answer 32

NH2—OH group in the middle

Question 33

what are the 3 essential SAR components for DHP CCBs?

Answer 33

1. dihydropyridine
2. R2 and R3 bulky groups
3. X ortho or meta electron withdrawing (2 rings need to be perpendicular)

Question 34

how does epinephrine bind to the adrenergic receptor?

Answer 34

epi amine binds to carb acid, the 2 OH groups bind to serines and there are pi bonds between rings

Question 35

what is the main structural difference between drugs that target B over alpha?

Answer 35

adding a bulky group around the nitrogen makes it prefer B because B receptors have a bigger pocket to accomodate

Question 36

which B blocker is most lipophillic? which is least? what is the implication of this?

Answer 36

most is propranolol, least is nadolol. Lipophillic may mean in crosses the BBB and in older patients can have more CNS effectives

Question 37

how must the substituent on the B blocker be wrt the oxygen in order to interact with the receptor?

Answer 37

para (directely across)