Identification and characterization of the ocular hypotensive efficacy of travoprost, a potent and selective FP prostaglandin receptor agonist, and AL-6598, a DP prostaglandin receptor agonist.
The structure-activity studies that led to the identification of travoprost, a highly selective and potent FP prostaglandin analog, and AL-6598, a DP prostaglandin analog, are detailed. In both series, the 1-alcohol analogs are very effective and are thought to be acting as prodrugs for the biologically active carboxylic acids. The efficacy of amide prodrugs depends on the degree of substitution and the size of the substituents. Selected compounds are profiled in vitro and in vivo preclinically. Clinical studies show that travoprost 0.004% (isopropyl ester) provided intraocular pressure control superior to timolol 0.5% when used as monotherapy in patients with open-angle glaucoma or ocular hypertension. In clinical studies, AL-6598 0.01% provided a sustained intraocular pressure reduction with q.d. application; b.i.d. provided greater intraocular pressure control. The acute and, apparently, conjunctival hyperemia associated with topical ocular AL-6598 can be attenuated while maintaining intraocular pressure-lowering efficacy by formulating with brimonidine.
Department of Medicinal Chemistry, Alcon Research Ltd., 6201 South Freeway, Fort Worth, TX 76134, USA. Mark.Hellberg@AlconLabs.com
Mark R
MR
Hellberg
Marsha A
MA
McLaughlin
Naj A
NA
Sharif
Louis
L
DeSantis
Tom R
TR
Dean
Evan P
EP
Kyba
John E
JE
Bishop
Peter G
PG
Klimko
Paul W
PW
Zinke
Robert D
RD
Selliah
George
G
Barnes
Joseph
J
DeFaller
Angela
A
Kothe
Theresa
T
Landry
E Kenneth
EK
Sullivan
Russell
R
Andrew
Alberta A
AA
Davis
Lewis
L
Silver
Michael V W
MV
Bergamini
Stella
S
Robertson
Alan L
AL
Weiner
Verney L
VL
Sallee
D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001082:Aqueous Humor / Q000187:drug effects; D002415:Cats; D003008:Cloprostenol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005902:Glaucoma, Open-Angle / Q000188:drug therapy*; D006168:Guinea Pigs; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects*; D008252:Macaca fascicularis; D008297:Male; D009798:Ocular Hypertension / Q000188:drug therapy; D011817:Rabbits; D016032:Randomized Controlled Trials as Topic; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin / Q000819:agonists*; D012449:Safety; D013329:Structure-Activity Relationship; D013999:Timolol / Q000627:therapeutic use; D000069557:Travoprost
C469387:AL 6598; D000959:Antihypertensive Agents; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor; D003008:Cloprostenol; D013999:Timolol; D015237:Dinoprost; D000069557:Travoprost; C036293:prostaglandin D2 receptor