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1

Electronic Resource

Phosphoryloxymethyl Carbamates and Carbonates—Novel Water-Soluble Prodrugs for Amines and Hindered Alcohols (1993)

Safadi, Muhammad ; Oliyai, Reza ; Stella, Valentino J.

Springer

Pharmaceutical research 10 (1993), S. 1350-1355

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ISSN: 1573-904X

Keywords: phosphoryloxymethyl carbonates ; phosphoryloxymethyl carbamates ; water-soluble prodrugs ; amines ; hindered alcohols

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Phosphoryloxymethyl carbonates and carbamates of the type R 1 R 2 X-CO-O-CH2-O-PO3 −2 (X = O or N) were evaluated as potentially novel water-soluble collapsible prodrugs for alcohols and amines. These were prepared by reaction of α-chloromethyl chloroformate with the starting alcohol or amine to give the corresponding α-chloromethyl carbonate or carbamate, respectively. Reaction with silver dibenzyl phosphate followed by debenzylation by hydrogenolysis gave the desired products. The aqueous chemical stability of the phosphoryloxymethylcarbonyl derivatives of 2-indanol (3a), β-(3,4-dimethoxyphenyl)ethylamine (3b), and benzocaine (3c) were evaluated. The aqueous hydrolysis of 3a – 3c resulted in regeneration of the parent alcohol or amines. As expected, the hydrolytic behaviors of these derivatives were found to differ from that of simple alkyl and aryl phosphomonoesters. The rates of hydrolysis were extremely rapid, with the dianionic phosphate species possessing a higher reactivity than the monoanionic species. This was attributed to the proximity of the phosphate group to the carbonyl moiety. The carbamate derivatives, 3b and 3c, displayed greater chemical stability compared to the carbonate derivative, 3a. Alkaline phosphatases-mediated hydrolysis of the phosphate ester bond in 3c led to a rapid cascade reaction resulting in regeneration of the parent amine, benzocaine. Although the alcohol derivative described here appeared to be too chemically unstable to be ideal as a prodrug, the derivatives of the amines might have some use. They are expected to be cleaved in vivo by alkaline phosphatases.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1018934200343

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2

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Metabolism and Pharmacokinetics of Novel Oral Prodrugs of 9-[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA) in Dogs (1997)

Shaw, Jeng-Pyng ; Sueoka, Cathy M. ; Oliyai, Reza ; [et al.]

Springer

Pharmaceutical research 14 (1997), S. 1824-1829

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ISSN: 1573-904X

Keywords: prodrug ; 9-[(R)-2-(phosphonomethoxy)propyl]adenine ; antiretroviral drug ; oral bioavailability

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. A series of prodrugs designed to enhance the oral bioavailability of the antiretroviral agent 9-[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA; 1) have been synthesized, including a bis-(acyloxymethyl) ester 2 and a series of bis-(alkoxycarbonyloxymethyl) esters 3-9. The in vitro biological stability andin vivo pharmacokinetics of these prodrugs were evaluated to support selection of a prodrug candidate for clinical evaluation. Methods. The in vitrobiological stability of the prodrugs was examined in dog tissues (intestinal homogenate, plasma and liver homogenate). The apparent half-lives were determined based on the disappearance of prodrug using reverse-phase HPLC with UV detection. Oral bioavailability of PMPA from each prodrug was determined in fasted beagle dogs. Concentrations of PMPA in plasma were determined by HPLC following fluorescence derivatization. Data for prodrugs were compared to historical data for intravenous PMPA. Results. All prodrugs were rapidly hydrolyzed in dog plasma and tissues (t1/2 〈 60 min). In fasted beagle dogs, bis-[(pivaloyloxy)methyl] PMPA (bis-POM PMPA) 2 had the highest oral bioavailability as PMPA (37.8 ± 5.1%). The oral bioavailabilities of PMPA from bis-(alkoxycarbonyloxymethyl) esters ranged from 16.0% to 30.7% and PMPA was the major metabolite formed. Conclusions. There was a correlation between oral bioavailability and intestinal stability of bis-(alkoxycarbonyloxymethyl) ester prodrugs (r2 = 0.96). Lipophilicity (log P) was not a good predictor of oral bioavailability. The most labile prodrugs in dog intestinal homogenates, bis-(n-butyloxycarbonyloxymethyl) PMPA 5 and bis-(neo-pentyloxycarbonyloxymethyl) PMPA 8 (t1/2 〈 5 min) had the lowest oral bioavailabilities. Based on good oral bioavailability (30.1%), chemical and intestinal stability bis-(isopropyloxycarbonyloxymethyl) PMPA (bis-POC PMPA) 4 was selected as a candidate for clinical evaluation.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1012108719462

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3

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The Importance of Structural Factors on the Rate and the Extent of N,O-acyl Migration in Cyclic and Linear Peptides (1995)

Oliyai, Reza ; Siahaan, Teruna J. ; Stella, Valentine J.

Springer

Pharmaceutical research 12 (1995), S. 323-328

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ISSN: 1573-904X

Keywords: acyl migration ; peptides ; cyclosporin ; stability

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract The chemistry associated with the process of N,O-acyl migration was explored in both cyclic and linear peptides under aqueous acid conditions. The importance of backbone cyclization and N-methylation of the peptide bond on the kinetics of N,O-acyl migration in a series of linear and cyclic peptides related in structure to cyclosporin A (CsA) were examined. The similarity in the chemical reactivity of the cyclic peptide [MeLeu (3-OH)]1-CsA and the corresponding linear peptide [Val-MeLeu (3-OH)-Abu], suggested that for this series, cyclization of the peptide backbone may not play an important role in controlling the kinetics of N,O-acyl migration. In contrast, the disparity in the chemical reactivity of tripeptides [Val-MeLeu (3-OH)-Abu] and [Val-Leu (3-OH)-Abu], indicated that N-methylation of amide bond significantly impacted the kinetics. Various hypothesis are proposed to account for this observation.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1016231913858

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4

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Effect of Carbonate Salts on the Kinetics of Acid-Catalyzed Dimerization of Adefovir Dipivoxil (2000)

Yuan, Lung-Chi ; Dahl, Terrence C. ; Oliyai, Reza

Springer

Pharmaceutical research 17 (2000), S. 1098-1103

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ISSN: 1573-904X

Keywords: adefovir dipivoxil ; carbonate salts ; dimerization ; formaldehyde ; pH-modifying agent ; chemical stability

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. The chemical stability and product(s) distribution of adefovir dipivoxil (ADV) was examined in the presence of soluble and insoluble carbonate salts. Methods. Chemical stability of ADV in the solid state at 60°C/30% RH was examined. Stability was also examined in the presence of excess formaldehyde vapor at 23°C/53% RH. ADV and its degradation product(s) were determined by reverse phase HPLC. Results. Addition of aqueous soluble carbonate salts, such as sodium carbonate, compromised the stability of ADV in solid state. However, aqueous insoluble carbonates, such as calcium carbonate and magnesium carbonate, enhanced the stability of ADV as compared to the control formulation. Pivalic acid, a degradation product of ADV, was shown to accelerate the degradation rate of ADV in solid state. The de-stabilizing effect of this acid on ADV stability was diminished in the presence of magnesium carbonate. Pivalic acid also increased the rate at which ADV dimers were formed in the presence of formaldehyde vapor. Addition of insoluble carbonates reduced the rate of formaldehyde-catalyzed dimerization of ADV. Conclusions. Addition of insoluble carbonate salts decreased the rate of degradation of ADV by minimizing the extent of formaldehyde-catalyzed dimerization in solid state.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1026457729708

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5

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Aryl Ester Prodrugs of Cyclic HPMPC. I: Physicochemical Characterization and In Vitro Biological Stability (1999)

Oliyai, Reza ; Shaw, Jeng-Pyng ; Sueoka-Lennen, Cathy M. ; [et al.]

Springer

Pharmaceutical research 16 (1999), S. 1687-1693

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ISSN: 1573-904X

Keywords: prodrug ; cyclic phosphonate ; reactivity ; salicylate esters ; cidofovir ; cyclic HPMPC ; nucleotides

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. The chemical, enzymatic, and biological stabilities and physical properties of a series of salicylate and aryl ester prodrugs of the antiviral agent, cyclic HPMPC, were evaluated to support the selection of a lead compound for clinical development. Methods. Chemical stabilities of the prodrugs in buffered solutions at 37°C were determined. Stability was also studied in the presence of porcine liver carboxyesterases (PLCE) at pH 7.4 and 25°C. Tissue stabilities were examined in both human and dog intestinal homogenates, plasmas and liver homogenates. Prodrug and product concentrations were determined by reverse phase HPLC. Results. Chemical degradation of the prodrugs resulted in the formation of both cyclic HPMPC and the corresponding HPMPC monoester. Chemical stability was dependent on the orientation of the exo-cyclic ligand; the equatorial isomers were 5.4- to 9.4-fold more reactive than the axial isomers. In the presence of PLCE, the salicylate prodrugs cleaved exclusively to give cyclic HPMPC and not the HPMPC monoester. In plasma, but not intestinal or liver homogenates, the salicylate esters of cyclic HPMPC cleaved readily with a rate dependent on the chain length of the alkyl ester substituent. Conclusions. The carboxylate function on the salicylate prodrugs of cyclic HPMPC provides an additional handle to chemically modify the lipophilicity, solubility and the biological reactivity of the prodrug. In tissue and enzymatic studies, the major degradation product is cyclic HPMPC. The salicylate ester prodrugs are attractive drug candidates for further in vivo evaluation.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1018945713623

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6

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Biexponential Decomposition of a Neuraminidase Inhibitor Prodrug (GS-4104) in Aqueous Solution (1998)

Oliyai, Reza ; Yuan, Lung-Chi ; Dahl, Terrence C. ; [et al.]

Springer

Pharmaceutical research 15 (1998), S. 1300-1304

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ISSN: 1573-904X

Keywords: neuraminidase inhibitor ; biexponential kinetics ; GS-4104 ; N, N-acyl migration ; heteronuclear multiple bond correlation NMR

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract Purpose. To examine the degradation kinetics and identify the degradation products of a neuraminidase inhibitor prodrug, GS-4104. Methods. Degradation was studied as a function of pH and temperature using a stability-indicating RP-HPLC assay. Degradation products were isolated by RP-HPLC and identified by NMR. Specific rate constants were calculated based on a scheme defined by product(s) analysis. Results. Three distinct degradation products were observed in the pH region studied (pH 2−8): isomer I, GS-4071, and isomer II. Isomer I resulted from the N, N-migration of the acetyl group. GS-4071 was formed by the hydrolysis of the ethyl ester. Both GS-4071 and isomer I degraded further to isomer II by N, N-acyl migration and ester hydrolysis, respectively. The N, N-acyl migration reaction was characterized using two dimensional heteronuclear multiple bond correlation (HMBC) NMR. The decomposition kinetics of GS-4104 follow a biexponential decay at pH 2−7. The degradation kinetics of GS-4104 at pH 4.0, 70°C were independent of the initial GS-4104 concentration. Conclusions. The degradation profile indicates that development of solution or solid dosage form of GS-4104 with adequate shelf-life stability at room temperature is feasible.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1011964529805

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7

Electronic Resource

Kinetics and Mechanism of Isomerization of Cyclosporin A (1992)

Oliyai, Reza ; Stella, Valentino J.

Springer

Pharmaceutical research 9 (1992), S. 617-622

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ISSN: 1573-904X

Keywords: cyclosporin A ; isomerization ; N,O-acyl migration ; isocyclosporin A ; cyclic peptide, peptide bond cleavage

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract The kinetics of isomerization of cyclosporin A to isocyclosporin A were studied in various nonaqueous solvents as a function of temperature and added methanesulfonic acid. The rate of isomerization was found to be acid-catalyzed over the acid concentration range studied. The choice of organic solvent significantly altered the rate of isomerization. For a series of alcohols, the rate was enhanced with increasing dielectric constant of the media, however, this correlation did not hold upon introduction of the dipolar aprotic solvent, tetrahydrofuran. Conversion of cyclosporin A to isocyclosporin A in tetrahydrofuran was found to contain diminished side reactions as compared to alcoholic solvents. The rate of conversion of isocyclosporin A to cyclosporin A was determined in aqueous buffers as a function of pH, buffer concentration, and temperature. The rates of conversion were extremely rapid compared to the forward reaction. Based on the pH dependencies of dilute solution reactivities, isocyclosporin A displayed a kinetically generated pK a value of 6.9 for the secondary amine moiety. From pH 8 to pH 10 the pH–rate profile plot is linear, with a slope approximately equal to unity, indicating apparent hydroxide ion catalysis. The break in pH–rate profile suggests a change in the rate-determining step upon protonation of isocyclosporin A. The rate of isomerization in plasma was comparable with that found in a pH 7.4 buffer solution, indicating that plasma proteins do not significantly alter the isomerization kinetics of isocyclosporin A to cyclosporin A.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1023/A:1015841824760

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