Med Chem - glaucoma part 2

Question 1

name 6 prostaglandin analogs for glaucoma

Answer 1

latanoprost
travoprost
tafluprost
unoprostone
bimatoprost
latanoprostene

Question 2

all the prostaglandin analogs are specifically derivatives of what?

Answer 2

PGF

Question 3

all the prostaglandin analogs indicated for glaucoma treatment are _______ modified analogs of ________

Answer 3

w (omega) chain modified analogs of PGF

w chain is the chain away from the carboxy group

Question 4

which prostaglandin analog has fluorinated w chain and what does this mean about its activity?

Answer 4

tafluprost AND travoprost

it has HIGH AFFINITY for PGF receptor

Question 5

how and why are latanoprost, travoprost, tafluprost, unoprostone, and bimatoprost prodrugs?

Answer 5

they all have their COOH group protected by either an amide or an ester

they will be hydrolyzed to reveal their hidden COOH by either corneal esterases or amidases

them being lipophilic enhances their absorption through the 1st layer of the corneal membrane - the epithelium - which is lipophilic

once hydrolyzed they are now hydrophilic with their COOH and can cross the next layer - THE STROMA

COOH is ESSENTIAL to bind the PGF receptor

Question 6

explain the layers of the corneal membrane and if they are lipophilic or hydrophilic

Answer 6

outermost layer is lipophilic - epithelium

middle = stroma - hydrophilic

most inner = endothelium - lipophilic

3 LAYERS
lipophilicity very important to cross the entire membrane. BUT COOH must be revealed to bind PGF receptor

Question 7

what is the “dual action” PG derivative

Answer 7

latanoprostene

Question 8

explain how latanoprostene has dual mechanism of action

Answer 8

when metabolized (hydrolyzed) produces latanoprostic acid (ACTIVE METABOLITE) and butanediol mononitrate

latanoprostic acid has same MOA as latanoprost – increased uveoscleral outflow

this butanediol mononitrate splits into 1,4-dutanediol AND NITRIC OXIDE

this nitric oxide is a vasodilator. stimulates cGMP which causes relaxation/vasodilation of the trabecular meshwork, which increases trabecular outflow!!!

Question 9

is latanoprostene a prodrug?

Answer 9

YES

esterified with a nitrate-containing butanol alcohol

Question 10

what is netarsudil

Answer 10

a rho kinase inhibitor (ROCK1/ROCK2)

FIRST IN CLASS

Question 11

is netarsudil a prodrug?

Answer 11

YES

hydrolyzed by corneal esterases into the active metabolite, which is a highly potent ROCK1/ROCK2 inhibitor

Question 12

where are ROCK1/ROCK2 highly expressed?

Answer 12

in the trabecular meshwork

Question 13

explain MOA of netarsudil

Answer 13

makes trabecular network more flexible. allows the fluid to flow through trabecular meshwork and into canal of schlemm

Question 14

does netarsudil itself have any pharmacological activity?

Answer 14

yes - moderate ROCK inhibition, but still considered a prodrug

Question 15

what is ROCKLATAN

Answer 15

combination product of netarsudil and latanoprost