3-Oxa-15-cyclohexyl prostaglandin DP receptor agonists as topical antiglaucoma agents.
A series of prostaglandin DP agonists containing a 3-oxa-15-cyclohexyl motif was synthesized and evaluated in several in vitro and in vivo biological assays. The reference compound ZK 118.182 (9beta-chloro-15-cyclohexyl-3-oxa-omega-pentanor PGF(2alpha)) is a potent full agonist at the prostaglandin DP receptor. Saturation of the 13,14 olefin affords AL-6556, which is less potent but is still a full agonist. Replacement of the 9-chlorine with a hydrogen atom or inversion of the carbon 15 stereochemistry also reduces affinity. In in vivo studies ZK 118.182 lowers intraocular pressure (IOP) upon topical application in the ocular hypertensive monkey. Ester, 1-alcohol, and selected amide prodrugs of the carboxylic acid enhance in vivo potency, presumably by increasing bioavailability. The clinical candidate AL-6598, the isopropyl ester prodrug of AL-6556, produces a maximum 53% drop in monkey IOP with a 1 microg dose (0.003% w/w) using a twice-daily dosing regime. Synthetically, AL-6598 was accessed from known intermediate 1 using a novel key sequence to install the cis allyl ether in the alpha chain, involving a selective Swern oxidative desilylation of a primary silyl ether in the presence of a secondary silyl ether. In this manner, 136 g of AL-6598 was synthesized under GMP conditions for evaluation in phase I clinical trials.
Hellberg
Mark R
MR
Department of Medicinal Chemistry, Alcon Research, Ltd., Pharmaceutical Products Research, 6201 South Freeway, Fort Worth, TX 76134, USA.
Conrow
Raymond E
RE
Sharif
Najam A
NA
McLaughlin
Marsha A
MA
Bishop
John E
JE
Crider
Julie Y
JY
Dean
W Dennis
WD
DeWolf
Kevin A
KA
Pierce
David R
DR
Sallee
Verney L
VL
Selliah
Robert D
RD
Severns
Bryon S
BS
Sproull
Steven J
SJ
Williams
Gary W
GW
Zinke
Paul W
PW
Klimko
Peter G
PG
D000287:Administration, Topical; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015237:Dinoprost / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005901:Glaucoma / Q000188:drug therapy*; D000882:Haplorhini; D007429:Intraocular Pressure / Q000187:drug effects; D015394:Molecular Structure; D011485:Protein Binding; D011817:Rabbits; D011982:Receptors, Prostaglandin / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
C470921:9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid; C469387:AL 6598; D000959:Antihypertensive Agents; D011982:Receptors, Prostaglandin; C067426:ZK 118182; D015237:Dinoprost