Potent HIV protease inhibitors containing a novel (hydroxyethyl)amide isostere.

A series of HIV protease inhibitors containing a novel (hydroxyethyl)amidosuccinoyl core has been synthesized. These peptidomimetic structures inhibit viral protease activity at low nanomolar concentrations (IC50 < 10 nM for HIV-1 protease). The inhibition constant (Ki) for inhibitor 19 was determined to be 7.5 pM against HIV-1 and 1.2 nM against HIV-2 proteases, respectively. Several compounds (19-24) inhibited HIV-1 replication in cell culture assays with 50% effective concentrations (EC50) = 3.7-35 nM. This series of inhibitors was found to exhibit poor bioavailability (< 10%) in the rat, following oral administration. The synthesis and biological properties of these compounds are discussed. In addition, an X-ray structure of one of these inhibitors (23) in complex with HIV-2 protease provides insight into the binding mode of this novel class of HIV protease inhibitors.

HPLC studies on leukotriene A4 obtained from the hydrolysis of its methyl ester.

Alkaline hydrolysis of leukotriene A4 methyl ester to leukotriene A4 was studied in either methanol or acetone. Hydrolysis in acetone yielded larger amounts of leukotriene A4 than similar hydrolysis in methanol. The maximum amount was obtained 60 minutes after the beginning of the hydrolysis. Leukotriene A4, as well as leukotriene B4 methoxy isomers were obtained from hydrolysis of leukotriene A4 methyl ester in methanol. It was found that initial leukotriene A4 methyl ester concentration affected the amount of LTA4 produced during the hydrolysis. The maximum concentration of leukotriene A4 was obtained by hydrolyzing solutions of 0.25 mg/ml leukotriene methyl ester in acetone. Spontaneous degradation of leukotriene A4 occurred when it was diluted with tris buffer. Addition of bovine serum albumin to the tris buffer significantly prolonged the half life of leukotriene A4.

Chemistry and positive inotropic effect of pelrinone and related derivatives. A novel class of 2-methylpyrimidones as inotropic agents.

A novel series of pyrimidine derivatives was synthesized and evaluated for positive inotropic activity. Inotropic and chronotropic effects were determined in vitro in cat papillary muscle and right atrium, respectively. Selected compounds were then evaluated in vivo in a dog heart failure model. Changes in ventricular dP/dt, heart rate, and blood pressure were monitored. Several of these agents produced relatively minor changes in heart rate. This class of agents demonstrated a varying degree of vasodilator effects concomitant with increases in ventricular contractility. The most potent analogues, 9, 48, and 49, were evaluated orally in conscious dogs with implanted Konisberg pressure transducers, and their effect on left ventricular dP/dt was compared with that of milrinone. Mechanistically, the agents of this novel class appear not to mediate their effect via beta-receptors or inhibition of Na+/K+-ATPase. A major component of their inotropic effect is mediated by the inhibition of cardiac phosphodiesterase (PDE)-Fr. III. This was clearly demonstrated by 9, 48, and 49. Compound 48 was found to be the most potent inhibitor of PDE-Fr. III from among the compounds tested in this assay.

Troponoids. 7. Chemistry and dopamine agonist activity of ciladopa and related aralkyltroponylpiperazines.

A series of N-aralkyltroponylpiperazine derivatives were synthesized and evaluated for dopaminergic activity in rats rendered hypokinetic by the bilateral injection of 6-hydroxydopamine (6-OHDA) into the anterolateral hypothalamus. Several members of the series were active, and a structure-activity relationship is presented. A few selected compounds were also evaluated with regard to their ability to induce contralateral rotational behavior in rats with a unilateral 6-OHDA-induced lesion of the nigrostriatal dopamine (DA) pathway and to suppress elevated serum prolactin levels. The compounds were compared to bromocriptine. Some of the more potent analogues were also assayed for their binding affinity to dopamine (DA) and alpha 1-adrenergic receptors. The results established that the potency of some of the compounds were comparable or superior to that of bromocriptine indicated that potent dopaminergic activity was dependent on the presence of both a substituted phenyl and a troponylpiperazine moiety, and confirmed that the dopaminergic activity depends on relative and absolute stereochemistry.

Troponoids. 6. Troponylpiperazines: a new class of dopamine agonists.

A series of alkyltroponylpiperazine derivatives was synthesized and evaluated for dopaminergic activity in rats rendered hypokinetic by the bilateral injection of 6-hydroxydopamine (6-OHDA) into the anterolateral hypothalamus. Several members of the series were active, and a structure-activity relationship is presented. A few selected compounds were also evaluated with regard to their ability to induce contralateral rotational behavior in rats with a unilateral 6-OHDA-induced lesion of the nigrostriatal dopamine pathway. The compounds were compared to bromocriptine. The results indicate that dopaminergic activity is very sensitive to small changes in the troponylpiperazine moiety.

Troponoids. 3. Synthesis and antiallergy activity of N-troponyloxamic acid esters.

A number of oxamic acid derivatives of tropones and tropolones were synthesized and their antianaphylactic activity was determined in passive paw anaphylaxis (PPA). Several of these esters possessed oral activity. A comparison of the effect on the biological activity of the esters and the corresponding acid and its salt is reported. The experiments suggesting a relationship between the activity and the bioavailability of the ester 19 are also described. A study of the fate of ester 19 in serum on oral or intravenous administration to rats and dogs is reported. In vitro results of the effect of the compounds 19, 45, and 45a on the activity of the guinea pig lung and beef heart phosphodiesterase are presented. The various factors that may contribute to the antiallergy activity of compounds of this series are discussed.

Prostaglandins. IV. Total syntheses of dl-11-deoxy PGE 1 and 13,14-dihydro derivatives of 11-deoxy PGE 1 , PGF 1 , and PGF 1 .

PIP: A photoannelation reaction between 2 alpha, beta-unsaturated ketones is described. The photoadduct was isolated and characterized by spectral analysis and was transformed into methoxy and acetoxy derivatives. Some mechanistic implications of photoannelation and the finding of a rearrangement product are discussed. Transformations of diketone to other prostanoic acid derivatives are also described. Structural formulas are depicted in a stepwise manner.^ieng

Prostaglandins II--an improved synthesis and structural proof of (plus or minus)-11-deoxyprostaglandin F-1-beta.

PIP: Reported here is an improved synthesis and physicochemical evidences for the stereochemical assignments of (+/-)-11-deoxyprostaglandin F1beta. The stereochemistry of asymmetric centers are established (configurations published) and confirmed by ozonolysis of the diacetoxy methyl ester XII, followed by decomposition of the oxonide with 30% hydrogen peroxide in acetic acid at 50 degrees over 40 hours: this gave a crude mixture. Esterification of the acidic product with diazomethane followed by chromatography yielded an acetoxy diester identical in all respects with that obtained from alcohol VII (pictured in text). This evidence assigns conclusively the stereochemistry at carbon atoms C-8, C-9, and C-12. In the compound under investigation, the mode of genesis of asymmetric center at C-15 is beyond stereochemical control and a mixture of stereoisomers is expected.^ieng