Synthesis of prostaglandin analogues, latanoprost and bimatoprost, using organocatalysis via a key bicyclic enal intermediate.

Two antiglaucoma drugs, bimatoprost and latanoprost, which are analogues of the prostaglandin, PGF2α, have been synthesized in just 7 and 8 steps, respectively. The syntheses employ an organocatalytic aldol reaction that converts succinaldehyde into a key bicyclic enal intermediate, which is primed for attachment of the required lower and upper side chains. By utilizing the crystalline lactone, the drug molecules were prepared in >99% ee.

Therapeutic uses of prostaglandin F(2α) analogues in ocular disease and novel synthetic strategies.

The pharmacological management of glaucoma and ocular hypertension has significantly changed over the last 18 years with the introduction of PGF2α analogues, more specifically latanoprost (6), travoprost (8), bimatoprost (10) and tafluprost (12). Prostanoids are currently the first-line medicines among ocular antihypertensive drugs in terms of efficacy, safety, patient compliance and medical economy. Their ability to effectively reduce intraocular pressure with once-per-day dosing, ocular tolerability comparable to timolol and general lack of systemic adverse effects have made them the mainstay of pharmacological therapy for glaucoma and ocular hypertension all over the world. The present review reports a novel, convergent and highly diastereoselective method for the synthesis of PGF2α analogues from the structurally advanced prostaglandin phenylsulfone (5Z)-(+)-15 and new ω-chain synthons. The biochemistry, clinical efficacy and side effects of four commercially available PGF2α analogues, currently used as first-line agents for reducing intraocular pressure in patients with glaucoma or ocular hypertension, are also discussed.

Stereocontrolled organocatalytic synthesis of prostaglandin PGF2α in seven steps.

Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction. Their biological activities and their complex molecular architectures have made prostaglandins popular targets for synthetic organic chemists for over 40 years. Prostaglandin analogues are widely used as pharmaceuticals and some, such as latanoprost, which is used to treat glaucoma, have become billion-dollar drugs. Previously reported syntheses of these compounds are quite lengthy, and every chemical step costs time and energy, generates waste and is accompanied by material losses. Using a new bond disconnection, here we report a concise synthesis of the most complex prostaglandin, PGF2α, with high levels of control of relative and absolute stereochemistry, and fewer steps. The key step is an aldol cascade reaction of succinaldehyde using proline organocatalysis to create a bicyclic enal in one step and an enantiomeric excess of 98%. This intermediate bicyclic enal is fully primed with the appropriate functionality for attachment of the remaining groups. Access to this bicyclic enal will not only render existing prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of related chemical structures around the ubiquitous five-membered ring motif, such as potentially therapeutic prostaglandin analogues.

A novel nitric oxide releasing prostaglandin analog, NCX 125, reduces intraocular pressure in rabbit, dog, and primate models of glaucoma.

PURPOSE: Nitric oxide (NO) is involved in a variety of physiological processes including ocular aqueous humor dynamics by targeting mechanisms that are complementary to those of prostaglandins. Here, we have characterized a newly synthesized compound, NCX 125, comprising latanoprost acid and NO-donating moieties. METHODS: NCX 125 was synthesized and tested in vitro for its ability to release functionally active NO and then compared with core latanoprost for its intraocular pressure (IOP)-lowering effects in rabbit, dog, and nonhuman primate models of glaucoma. RESULTS: NCX 125 elicited cGMP formation (EC(50) = 3.8 + or - 1.0 microM) in PC12 cells and exerted NO-dependent iNOS inhibition (IC(50) = 55 + or - 11 microM) in RAW 264.7 macrophages. NCX 125 lowered IOP to a greater extent compared with equimolar latanoprost in: (a) rabbit model of transient ocular hypertension (0.030% latanoprost, not effective; 0.039% NCX 125, Delta(max) = -10.6 + or - 2.3 mm Hg), (b) ocular hypertensive glaucomatous dogs (0.030% latanoprost, Delta(max)= -6.7 + or - 1.2 mm Hg; 0.039% NCX 125, Delta(max) = -9.1 + or - 3.1 mm Hg), and (c) laser-induced ocular hypertensive non-human primates (0.10% latanoprost, Delta(max) = -11.9 + or - 3.7 mm Hg, 0.13% NCX 125, Delta(max) = -16.7 + or - 2.2 mm Hg). In pharmacokinetic studies, NCX 125 and latanoprost resulted in similar latanoprost-free acid exposure in anterior segment ocular tissues. CONCLUSIONS: NCX 125, a compound targeting 2 different mechanisms, is endowed with potent ocular hypotensive effects. This may lead to potential new perspectives in the treatment of patients at risk of glaucoma.

New prostaglandin derivative for glaucoma treatment.

A hydrogen sulphide-releasing derivative of latanoprost acid (ACS 67) was synthesized and tested in vivo to evaluate its activity on reduction of intraocular pressure and tolerability. Glutathione (GSH) and cGMP content were also measured in the aqueous humour. The increased reduction of intraocular pressure, with a marked increase of GSH and cGMP and the related potential neuroprotective properties, make this compound interesting for the treatment of glaucoma. This is the first time that an application of a hydrogen sulphide-releasing molecule is reported for the treatment of ocular diseases.

Synthesis of prostaglandin F ethanolamide by prostaglandin F synthase and identification of Bimatoprost as a potent inhibitor of the enzyme: new enzyme assay method using LC/ESI/MS.

Prostaglandin (PG) D(2) ethanolamide (prostamide D(2)) was reduced to 9alpha,11beta-PGF(2) ethanolamide (9alpha,11beta-prostamide F(2)) by PGF synthase, which also catalyzes the reduction of PGH(2) and PGD(2) to PGF(2alpha) and 9alpha,11beta-PGF(2), respectively. These enzyme activities were measured by a new method, the liquid chromatographic-electrospray ionization-mass spectrometry (LC/ESI/MS) technique, which could simultaneously detect the substrate and all products. PGF(2alpha), 9alpha,11beta-PGF(2), PGD(2), PGH(2), 9alpha,11beta-prostamide F(2), and prostamide D(2) were separated on a TSKgel ODS 80Ts column, ionized by electrospray, and detected in the negative mode. Selected ion monitoring (SIM) of m/z 353 ([M-H](-)), 353 ([M-H](-)), 351 ([M-H](-)), 333 ([M-H-H(2)O](-)), 456 ([M+59](-)), and m/z 358 ([M-37](-)) was used for quantifying PGF(2alpha), 9alpha,11beta-PGF(2), PGD(2), PGH(2), 9alpha,11beta-prostamide F(2), and prostamide D(2), respectively. The detection limit for PGF(2alpha) and 9alpha,11beta-PGF(2) was 0.01pmol; that for PGH(2) and PGD(2), 0.1pmol; and that for prostamide D(2) and 9alpha,11beta-prostamide F(2), 0.5 and 0.03pmol, respectively. The LC/ESI/MS technique for measuring PGF synthase activity showed higher sensitivity than other methods. Using this method, we found that Bimatoprost, the ethyl amide analog of 17-phenyl-trinor PGF(2alpha) and an anti-glaucoma agent, inhibited all three reductase activities of PGF synthase when used at a low concentration. These results suggest that Bimatoprost also behaves as a potent PGF synthase inhibitor in addition to having prostamide-like activity.

Studies on ocular inflammation and development of a prostaglandin analogue for glaucoma treatment.

This review summarizes the Ernst H. Bárány Prize Lecture given at the meeting of the International Society of Eye Research in Geneva 2002. In the paper the path from the author's early studies on neurogenic inflammation in the eye to the search for a suitable prostaglandin analogue for glaucoma treatment, and the development of latanoprost are described. In particular the solution to the nociceptive and hyperemic side-effects of naturally occurring prostaglandins in the eye, the mechanism of action of FP prostanoid receptor agonists as well as the selection of dose for glaucoma treatment are discussed. In addition, pharmacokinetical aspects of latanoprost, and the melanogenic side-effect of prostaglandins in the iris are addressed. The paper is primarily focused on studies performed by the author and complete reference to other previous, or contemporary studies is therefore not always given as the purpose is not to present a comprehensive review article.

A practical synthesis and biological evaluation of 9-halogenated PGF analogues.

A series of 9-halo PGF analogues 1-2 and 5-13 were synthesized and biologically evaluated. Among the compounds, 2 was the best EP2-receptor agonist. A practical method of synthesizing 2 via the Julia olefination of an aldehyde 3 with an optically active sulfone 4, which was prepared by Sharpless asymmetric epoxidation of 15, was developed. Other 9-halogenated PGF analogues were synthesized essentially by the same procedure and evaluated. The absolute configuration of 16-OH of 2 was determined as S by the X-ray analysis of a salt consisting of a 1/1 molar ratio of 2 and L-lysine.

Development of a highly selective EP2-receptor agonist. Part 2: identification of 16-hydroxy-17,17-trimethylene 9beta-chloro PGF derivatives.

Further chemical modification of 1a and 2 was undertaken to identify a more chemically stable selective EP2-receptor agonist for development as a clinical candidate. 9beta-chloro PG analogues 4a-e and 5a, c-e were found to be potent and selective EP2-receptor agonists. Among them, the compound 4aLy, which is a chemically stabilized lysine salt of 4a, exhibited an excellent profile both in biological activities and physicochemical properties. The agonist 4aLy was found to suppress uterine motility in anesthetized pregnant rats, while PGE2 stimulated uterine motility. Structure-activity relationships (SARs) are discussed.

Synthesis and biological evaluation of prostaglandin-F alkylphosphinic acid derivatives as bone anabolic agents for the treatment of osteoporosis.

A series of novel C(1) alkylphosphinic acid analogues of the prostaglandin-F family have been evaluated at the eight human prostaglandin receptors for potential use in the treatment of osteoporosis. Using molecular modeling as a tool for structure-based drug design, we have discovered that the phosphinic acid moiety (P(O)(OH)R) behaves as an isostere for the C(1) carboxylic acid in the human prostaglandin FP binding assay in vitro and possesses enhanced hFP receptor selectivity when compared to the parent carboxylic acid. When evaluated in vivo, the methyl phosphinic acid analogue (4b) produced a bone anabolic response in rats, returning bone mineral volume (BMV) [corrected], to intact levels in the distal femur in the ovariectomized rat (OVX) model. These results suggest that prostaglandins of this class may be useful agents in the treatment of diseases associated with bone loss.

An efficient synthesis of 3-hetero-13,14-dihydro prostaglandin F1alpha analogues.

[structure: see text]. A new class of 3-hetero-13,14-dihydro prostaglandin F(1)(alpha) analogues was synthesized from a common intermediate. The latter was constructed via a two-step, three-component process. The lower chain, containing the 15-(phenoxymethyl) group, was synthesized in enantiopure form using Jacobsen's (salen)Co-catalyzed kinetic resolution of a terminal epoxide with phenol.

Mass spectra of tert-butyldimethylsilyl ether derivatives of the major metabolite of prostaglandin F.

The EI mass spectra of four tert-butyldimethylsilyl ether derivatives of the major metabolite of prostaglandins F1 alpha and F2 alpha (PGF-M) are presented and discussed. Proposed ion assignments and fragmentation pathways are based on substituent shifts, on data from a deuterium-labeled methoxime analog, and on the analysis of collision-induced dissociation spectra of selected ions. Fragment ions suitable for identification and quantification work are proposed.

Prostaglandin photoaffinity probes: synthesis and biological activity of azide-substituted 16-phenoxy- and 17-phenyl-PGF2 alpha prostaglandins.

The development of a prostaglandin PGF2 alpha photoaffinity probe led to the synthesis and biological evaluation of azide-substituted 17-phenyl-18,19,20-trinorprostaglandin F2 alpha and 16-phenoxy-17,18,19,20-tetranorprostaglandin F2 alpha derivatives. Two approaches for the preparation of iodinated versions of these prostaglandins were evaluated: (1) iodination of a phenyl azide bearing an activating hydroxyl group and (2) iodination of an aniline precursor to the phenyl azide group and subsequent conversion of the aniline to the phenyl azide. In the first approach, 17-(4-azido-2-hydroxyphenyl)-18,19,20-trinorprostaglandin F2 alpha, 16-(5-azido-3-hydroxyphenoxy)-17,18,19,20-tetranorprostaglandin F2 alpha, and 16-(4-azido-2-hydroxyphenoxy)-17,18,19,20-tetranorprostaglandin F2 alpha were prepared by using the Corey synthesis, but were biologically inactive presumably as a result of the hydrophilic phenolic hydroxyl group. In the second approach, the iodination of a 17-(4-aminophenyl)-18,19,20-trinorprostaglandin F2 alpha derivative delivered 17-(4-azido-3-iodophenyl)-18,19,20-trinorprostaglandin F2 alpha, which exhibited competitive binding with natural [3H]PGF2 alpha to ovine luteal cells and to plasma membranes of bovine corpora lutea. [125I]-17-(4-Azido-3-iodophenyl)-18,19,20-trinorprostaglandin F2 alpha was utilized in a preliminary photoaffinity cross-linking experiment.

Structure-activity studies of 16-methoxy-16-methyl prostaglandins.

The synthesis of the pure diastereoisomer of 16-methoxy-16-methyl-PGF2 alpha, -PGE2, and -PGE1 is described. The absolute configuration of C-16 was established by chemical methods, while the absolute C-15 configurations of the diastereoisomers were assigned tentatively on the basis of their chromatographic behavior and NMR spectra. The synthetic prostaglandin analogues were evaluated for antisecretory, antifertility, and diarrheogenic effects. Both the C-15 and C-16 configurations were found to be critical for the biological activities. These studies indicate that the introduction of the methyl and methoxy groups at C-16 into the prostaglandin analogues markedly increases the ratio of antisecretory to diarrheogenic action. One of the PGE1 derivatives, 9f(15 alpha, 16R) (MDL 646, mexiprostil), was selected for further pharmacological evaluation and is currently under clinical investigation.

Synthesis and biological properties of 16(S)-amino-PGF2 alpha methyl ester.

A synthesis of 16-amino-derivatives of PGF2 alpha is reported. Introduction of an amino group into position 16 of PGF2 alpha has decreased the sensitivity of the compound to metabolic degradation. 16(S)-amino-PGF2 alpha methyl ester shows high abortifacient activity with reduced diarrhoeic side effect.