Thioether benzenesulfonamide inhibitors of carbonic anhydrases II and IV: structure-based drug design, synthesis, and biological evaluation.
A novel series of potent thioether benzenesulfonamide inhibitors of carbonic anhydrases II and IV was discovered using structure-based drug design. Synthesis, structure-activity relationship, and optimization of physicochemical properties are described. Low nanomolar potency was achieved, and selected compounds with improved thermodynamic solubility showed promising in vitro inhibition of carbonic anhydrase activity in rabbit iris ciliary body homogenate.
Vernier
William
W
Pfizer Global Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, CA 92121, USA. william.f.vernier@pfizer.com
Chong
Wesley
W
Rewolinski
David
D
Greasley
Samantha
S
Pauly
Thomas
T
Shaw
Morena
M
Dinh
Dac
D
Ferre
Rose Ann
RA
Meador
James W
JW
Nukui
Seiji
S
Ornelas
Martha
M
Paz
Robert L
RL
Reyner
Eric
E
D000818:Animals; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D011817:Rabbits; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000096926:Benzenesulfonamides
D024402:Carbonic Anhydrase II; D002257:Carbonic Anhydrase Inhibitors; D013440:Sulfides; D013449:Sulfonamides; D000096926:Benzenesulfonamides