Design, synthesis, and evaluation of NO-donor containing carbonic anhydrase inhibitors to lower intraocular pressure.
The antiglaucoma drugs dorzolamide (1) and brinzolamide (2) lower intraocular pressure (IOP) by inhibiting the carbonic anhydrase (CA) enzyme to reduce aqueous humor production. The introduction of a nitric oxide (NO) donor into the alkyl side chain of dorzolamide (1) and brinzolamide (2) has led to the discovery of NO-dorzolamide 3a and NO-brinzolamide 4a, which could lower IOP through two mechanisms: CA inhibition to decrease aqueous humor secretion (reduce inflow) and NO release to increase aqueous humor drainage (increase outflow). Compounds 3a and 4a have shown improved efficacy of lowering IOP in both rabbits and monkeys compared to brinzolamide (2).
La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States.
Qinhua
Q
Huang
La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States.
Eugene Y
EY
Rui
La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States.
Morena
M
Cobbs
La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States.
Dac M
DM
Dinh
La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States.
Hovhannes J
HJ
Gukasyan
La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States.
Jennifer A
JA
Lafontaine
La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States.
Saurabh
S
Mehta
La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States.
Brian D
BD
Patterson
La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States.
David A
DA
Rewolinski
La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States.
Paul F
PF
Richardson
La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States.
Martin P
MP
Edwards
D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D015195:Drug Design; D005901:Glaucoma / Q000188:drug therapy; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D020030:Nitric Oxide Donors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D013843:Thiazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D013876:Thiophenes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
D002257:Carbonic Anhydrase Inhibitors; D020030:Nitric Oxide Donors; D013449:Sulfonamides; D013843:Thiazines; D013876:Thiophenes; C111827:brinzolamide; C062765:dorzolamide