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.
Hellberg
Mark R
MR
Department of Medicinal Chemistry, Alcon Research Ltd., 6201 South Freeway, Fort Worth, TX 76134, USA. Mark.Hellberg@AlconLabs.com
McLaughlin
Marsha A
MA
Sharif
Naj A
NA
DeSantis
Louis
L
Dean
Tom R
TR
Kyba
Evan P
EP
Bishop
John E
JE
Klimko
Peter G
PG
Zinke
Paul W
PW
Selliah
Robert D
RD
Barnes
George
G
DeFaller
Joseph
J
Kothe
Angela
A
Landry
Theresa
T
Sullivan
E Kenneth
EK
Andrew
Russell
R
Davis
Alberta A
AA
Silver
Lewis
L
Bergamini
Michael V W
MV
Robertson
Stella
S
Weiner
Alan L
AL
Sallee
Verney L
VL
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