Synthesis and evaluation of γ-lactam analogs of PGE2 as EP4 and EP2/EP4 agonists.

To identify topically effective EP4 agonists and EP2/EP4 dual agonists with excellent subtype selectivity, further optimization of the 16-phenyl ω-chain moiety of the γ-lactam 5-thia prostaglandin E analog and the 2-mercaptothiazole-4-carboxylic acid analog were undertaken. Rat in vivo evaluation of these newly identified compounds as their poly (lactide-co-glycolide) microsphere formulation, from which sustained release of the test compound is possible, led us to discover compounds that showed efficacy in a rat bone fracture healing model after its topical administration without serious influence on blood pressure and heart rate. A structure-activity relationship study is also presented.

Discovery of an 8-aza-5-thiaProstaglandin E1 analog as a highly selective EP4 receptor agonist.

For the purpose of discovering an orally available EP4 subtype-selective agonist, a series of 8-aza prostaglandin E(1) (PGE(1)) analogs were synthesized and evaluated for their affinity for PGE(2) receptor subtypes. Additionally, the structure-activity relationships of these compounds were studied. Among the tested compounds, the 8-aza PGE(1) analog 6 and 8-aza-5-thiaPGE(1) analog 12 had highly potent EP4 receptor affinity, good functional activity, and excellent subtype-selectivity. Furthermore, these analogs demonstrated good stability in human liver microsomes. As a result, we concluded that these two series of 8-aza PGE(1) analogs could be promising chemical leads for an orally available EP4 subtype-selective agonist.

Discovery of orally available 8-aza-5-thiaProstaglandin E1 analogs as highly selective EP4 agonists.

Analogs 8-aza-16-aryl prostaglandin E(1) (PGE(1)) and 8-aza-5-thia-16-arylPGE(1) were synthesized and evaluated with respect to their subtype receptor affinity and EP4 agonist activity for the purposes of identifying subtype-selective EP4 agonists that demonstrate oral efficacy. Using an inhibition assay of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production in rats, representative compounds were evaluated for their pharmacokinetic profiles and in vivo efficacy. Structure-activity relationships (SARs) were characterized and presented. Of the compounds tested, several demonstrated better oral exposure and/or in vivo efficacy compared with the previously reported analog 2a.

Dual modulation of urinary bladder activity and urine flow by prostanoid EP3 receptors in the conscious rat.

BACKGROUND AND PURPOSE: Cyclooxygenase inhibitors function to reduce levels of prostaglandin E(2) (PGE(2)) and are broadly efficacious in models of bladder overactivity. We therefore investigated a regulation of urinary bladder function in conscious rats by modulation of the EP(3) receptor for PGE(2). EXPERIMENTAL APPROACH: The activity of the EP(3) receptor agonist GR63799X, and EP(3) receptor antagonists, CM9 and DG041, at recombinant EP(3) receptors was evaluated in vitro. In vivo, intraduodenal dosing during conscious, continuous-filling cystometry of spontaneously hypertensive rats was utilized to determine the urodynamic effect of EP(3) receptor modulation. KEY RESULTS: GR63799X dose-dependently (0.001-1 mg x kg(-1)) reduced bladder capacity, as indicated by a reduction in both the micturition interval and volume of urine per void. In contrast, CM9 (10 and 30 mg x kg(-1)) and DG041 (30 mg x kg(-1)) enhanced bladder capacity, as indicated by significantly longer micturition intervals and larger void volumes. CM9 and DG041 inhibited the responses to GR63799X supporting the in vivo activity of these pharmacological agents at the EP(3) receptor. In addition to its effect on bladder capacity, GR63799X increased endogenous urine production. Intra-arterial infusion of saline mimicked the enhancement of urine flow observed with GR63799X, and the response was inhibited by CM9. CONCLUSIONS AND IMPLICATIONS: These data support the EP(3) receptor as a modulator of urinary bladder activity in the conscious rat, and in addition, indicate a role for EP(3) receptor activity in regulating urine flow.

Design and synthesis of a selective EP4-receptor agonist. Part 3: 16-phenyl-5-thiaPGE(1) and 9-beta-halo derivatives with improved stability.

To identify a new selective EP4-agonist with improved chemical stability, further chemical modification of those reported previously was continued. We focused our attention on chemical modification of the alpha chain of 3,7-dithiaPGE(1) and selected 5-thiaPGE(1) as a new chemical lead. Introduction of an optimized omega chain to the 5-thiaPG skeleton afforded m-methoxymethyl derivative 33a, which showed the most potent EP4-receptor agonist activity and good subtype-selectivity both in vitro and in vivo. 9beta-HaloPGF derivatives were also synthesized and biologically evaluated in an attempt to block self-degradation of the beta-hydroxyketone moiety. Among these series, and 39b showed potent agonist activity and good subtype-selectivity. Structure-activity relationships (SARs) are also discussed.

[Total synthesis and properties of prostaglandins. XXXVIII. Synthesis of 11-deoxyprostaglandin-E1 derivatives with amino acids and amines]. / Total'nyi sintez i svoistva prostaglandinov. XXXVIII. Sintez proizvodnykh 11-dezoksiprostaglandina-D1 s aminokislotami i aminami.

In order to study the physiological functions of 11-deoxyprostaglandin E1-alpha, a series of its amide derivatives with amino acids and some amines were synthesized using mixed anhydride technique. The myotropic properties of newly synthesized compounds were investigated.

[Total synthesis and properties of prostaglandins. XXI. Synthesis of a 4,4-dimethyl-4-sil analog of 11-deoxyprostaglandin E1]. / Total'nyi sintez i svoistva prostaglandinov. XXI. Sintez 4,4-dimetil-4-sila-analoga 11-dezoksiprostaglandina E1.

Total synthesis of a new prostaglandin analogue, 11-deoxy-4,4-dimethyl-4-sil-prostaglandin E1, is carried out through synthesis of a silicon-containing alpha-chain precursor and a 2-substituted cyclopentenone derivative followed by their cuprate-induced interaction.

Synthesis and gastric antisecretory properties of allenic 16-phenoxy-omega-tetranor prostaglandin E analogs.

In order to improve the modest oral activity of PGE2 as an inhibitor of gastric acid secretion, analogs were prepared and tested orally in histamine-challenged rats. Insertion of a double bond at C-4, resulting in the 4,5-allene analog of PGE1, gave a small increase in activity. Introduction of the omega-tetranor-16-phenoxy lower sidechain, a modification known to enhance activity in the PGF series, gave an eight-fold increase in activity. The analog having both modifications (enprostil, 2) showed a six hundred-fold increase in oral antisecretory activity over PGE2, which may reflect a potentiation effect. Modification of enprostil at C-1 (various esters) and at C-11 (11-methyl, 11-deoxy) generally resulted in compounds of high activity while modifications at other sites generally resulted in significant reductions in activity.

Syntheses of [11C]methyl esters of prostaglandins D2 and E2.

Prostaglandins (PG) are endogenous compounds that have been extensively studied by various techniques. In this paper, the syntheses of methyl esters of PGD2 and PGE2, labelled with 11C for PET investigations, are reported. The prostaglandin was esterified via its carboxylate anion, with [11C]methyl iodide as alkylating reagent, in a dimethyl sulphoxide-dimethylformamide mixture. To minimize the base-catalysed degradations, the carboxylate anion was generated in situ by use of tetramethylpiperidine. The radiochemical yield, including purification, was 70%, with a total synthesis time of 20-25 min counted from the end of the [11C]methyl iodide synthesis.

Synthesis and gastrointestinal pharmacology of a 3E,5Z diene analogue of misoprostol.

A stereospecific synthesis and the gastric antisecretory and diarrheal activity of a 3E,5Z diene analogue of misoprostol are described. The key intermediate in the synthesis was an alpha chain truncated acetylene that was obtained by a cuprate/enolate capture procedure on the corresponding cyclopentenone. Palladium-catalyzed coupling of the acetylene with methyl 4-iodo-3(E)-butenoate provided the conjugated enyne. Although selective hydrogenation of the enyne with Lindlar catalyst failed, the desired 3E,5Z diene was obtained with P-2 nickel as catalyst. The diene was about 3 times more potent than misoprostol in inhibiting gastric acid secretion in dogs and also in producing diarrhea in rats.

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.

11-Deoxy-11 alpha,12 alpha-methanoprostaglandin E2, a potent, short-acting bronchodilator.

11-Deoxy-11 alpha,12 alpha-methanoprostaglandin E2 (1b) and the corresponding methyl ester 7a were highly potent, but short acting, bronchodilators both by the intravenous (80 and 10 times PGE2, respectively) and aerosol (2 and approximately 1 times PGE2) routes, as measured by the Konzett-Rössler assay. The 11 beta,12 beta-methano compound 15a was two orders of magnitude less active than 7a. In rhesus monkeys anesthetized by aerosol administration, 1b was 10-50% as potent as, and had a duration of action similar to, PGE1 in the inhibition of methacholine-induced increases in airway resistance. At doses effective in preventing the methacholine response, 1b increased the heart rate (less than or equal to 30%) and precipitated mild upper airway irritation.

Azaprostaglandins. Synthesis and antiulcer activity of 11-deoxy-8-azaprostaglandin analogues.

We describe the synthesis and the antiulcer activity of new 11-deoxy-8-aza-PGE1 analogues (III a) and its C15-epimer (III b), (IV a) and its C15-epimer (IV b), featured by a triple bond in place of the C13-C14 trans double bond and a 16,16-dimethyl-17-oxabutyl omega-chain, respectively.

Synthesis and gastric antisecretory properties of 4,5-unsaturated derivatives of 15-deoxy-16-hydroxy-16-methylprostaglandin E1.

The synthesis and gastric antisecretory activities of the delta 4,5-cis, delta 4,5-trans, and 4,5-acetylenic analogues of 15-deoxy-16-hydroxy-16-methyl prostaglandin E1 methyl ester are described. The key step in the preparation of these compounds involved the stereospecific conjugate addition of a cuprate reagent to the appropriate cyclopentenones. Although the trans and acetylenic derivatives were weak inhibitors of gastric acid secretion, the cis olefin was more potent and longer acting than the saturated parent compound. Selectivity with respect to unwanted diarrheagenic effects was found to be improved over that of both the parent 16-hydroxy compound and the reference standards, (15S)-15-methyl- and 16,16-dimethylprostaglandin E2.

Synthesis of [3H]- and -[14C]-labeled sulprostone.

The synthesis of N-methanesulfonyl 16-phenoxy-omega-tetranor PGE2 carboxamide (sulprostone--CP-34,089/ZK-57,671) labeled with tritium and carbon-14 is described. Sulprostone labeled with tritium in the phenoxy moiety by means of catalytic hydrogenolysis was obtained in a 17% radiochemical yield with a specific activity of 1.0 Ci/mmol. The methanesulfonamide-14C derivative of sulprostone was prepared from methyl-14C iodide in an 11.8% radiochemical yield having a specific activity of 18.8 mCi/mmol.

Omega chain methylated analogs of PGF2 alpha and PGE2.

Our previously published prostaglandin (PG) synthesis route, in which the omega-chain is added in the penultimate step, provides facile access to a wide variety of omega-chain variant PG analogs. Each series requires only the synthesis of the appropriate methylated acylphosphonate for the Emmons' condensation. The syntheses of analogs bearing the following methylation patterns are detailed: 15-Me; 17,17-(Me) 2; 17, 17, 20-(Me) 3; 18, 18, 20-(Me) 3; 15, 18, 18, 20-(Me) 4; and 15-OMe-18, 18, 20- (Me) 3. The well-known 16., 16-dimethyl prostaglandins have also been prepared by this sequence. The synthesis of 16, 16-tetramethylene-PG analogs is also described.