Raymond E. Conrow

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.

A convergent route to calcitriol lactone via reductive cleavage of an enantiopure glycidyl ether

Abstract Reductive cleavage of the ((1-methyl-1-methoxy)ethyl) ether of (S)-2-methylglycidol with lithium 4,4′-di-t-butylbiphenylide, addition of aldehyde 3 to the resulting β-lithioalkoxide, followed by acidic hydrolysis, yields the advanced (23S,25R)-calcitriol lactone intermediate 4 plus its 23R epimer (∼1:1, 69%).

A transaminative synthesis of 9-amino-9-fluorenecarboxylic acid esters

Abstract The benzyl imines of several fluorenones were treated with base, followed by methyl chloroformate, to introduce the carbomethoxy group at the 9-fluorenyl position. Imine hydrolysis afforded the title compounds. The reaction was readily conducted on a 30-g scale.

(5Z,11Z,15R)-15-Hydroxyeicosa-5,11-dien-13-ynoic acid: A stable isomer of 15(S)-HETE that retains key vasoconstrictive and antiproliferative activity.

15(S)-Hydroxyeicosa-(5Z,8Z,11Z,13E)-tetraenoic acid (15(S)-HETE) is a metabolite of arachidonic acid that elicits a number of biological effects including vasoconstriction and angiogenesis. (5Z,11Z,15R)-15-Hydroxyeicosa-5,11-dien-13-ynoic acid (HETE analog 1) is a synthetic isomer of 15(S)-HETE that is much more stable to autoxidation. Using isometric recording of isolated pulmonary arteries from male and female rabbits, HETE analog 1 and 15(S)-HETE were found to elicit concentration-dependent contractions that were slightly greater in females compared to males. The maximal response in females was greater with 15(S)-HETE. HETE analog 1 and 15(S)-HETE increased [(3)H]-thymidine incorporation in vascular smooth muscle cells cultured from male rabbit pulmonary arteries; both the maximal response and potency were greater with 15(S)-HETE. In contrast, HETE analog 1 produced a concentration-dependent inhibition in proliferation and migration of human hormone-independent prostate carcinoma PC-3 cells. The protocol for synthesis of HETE analog 1 is reported. The stability of this substance and its similar biological profile to 15(S)-HETE support future studies in eicosanoid research.