Lipophilic, Acid-Stable, Adenosine Deaminase-Activated Anti-HIV Prodrugs for Central Nervous System Delivery. 3. 6-Amino Prodrugs of 2‘-β-Fluoro-2‘,3‘-dideoxyinosine

Abstract

A series of 6-substituted amino analogs of 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl) purines (F-ddN) has been synthesized and characterized with the objective of finding compounds which might be superior to existing drugs for the treatment of HIV in the central nervous system. These compounds are intended to be more lipophilic than the currently approved anti-HIV drugs for better blood-brain barrier penetration. Subsequent adenosine deaminase (ADA)-catalyzed hydrolysis of these prodrugs in the brain is expected to produce the anti-HIV agent, 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)hypoxanthine (F-ddI). The new compounds, synthesized from the corresponding 6-chloro analog, include F-ddN which contain methylamino, ethylamino, dimethylamino, hydroxylamino, methoxyamino, benzyloxyamino, hydrazino, and nitro substituents in the 6-position. The 6-nitro analog was isolated as an unexpected product during the preparation of the 6-chloro derivative. Among the analogs with anti-HIV activity, the ethylamino and dimethylamino compounds are ca. 100 times more lipophilic than ddI or F-ddI. As expected, 2'-fluoro substitution protects the compounds from acid-catalyzed glycosylic cleavage. Only the hydroxylamino and nitro analogs underwent any nonenzymatic hydrolysis at pH 1.0 or 7.4. This reaction, however, results in hydrolysis of the group in the 6-position rather than glycosylic bond cleavage. ADA catalyzes the hydrolysis of the 6-substituents at rates which vary from slightly slower (NO2, 1.7x) to much slower (NHEt, 5000x) than F-ddA. The 6-dimethylamino analog is the only compound which possesses anti-HIV activity (ED50 18 microM) without ADA hydrolysis. With the exception of the two inactive alkoxyamino compounds, the other prodrugs exhibited cellular protection in the HIV-1/PHA-PBM system with IC50 potencies of 7-40 microM.

Nucleoside Synthesis Mediated by Glycosyl Transferring Enzymes

“…Subsequent ADA-catalyzed hydrolysis of these prodrugs in the brain is expected to produce the anti-HIV agent, 9-(2,3-dideoxy-2-fluoro-␤-D-threo-pentofuranosyl)hypoxanthine. This hypothesis is proved by in vitro ADAcatalyzed hydrolysis of 6-substituted amino analogs at prodrug concentration (50 M) (70).…”

“…Along with deamination, AMPDA also catalyzes dechlorination and demethylation of the purine ribosides and enantioselective deamination of carbocyclic purine nucleosides to give the corresponding optically active 6-oxopurine derivatives (69). Prodrugs, 6-substituted amino analogs of 9-(2,3-dideoxy-2-fluoro-␤-D-threo-pentofuranosyl)purines have been synthesized with the objective of finding compounds which might be superior to existing drugs for the treatment of HIV in the central nervous system because these compounds are intended to be more lipophilic than the currently approved anti-HIV drugs for better blood brain barrier penetration (70). Subsequent ADA-catalyzed hydrolysis of these prodrugs in the brain is expected to produce the anti-HIV agent, 9-(2,3-dideoxy-2-fluoro-␤-D-threo-pentofuranosyl)hypoxanthine.…”

Absorption and Intestinal Metabolism of Purine Dideoxynucleosides and an Adenosine Deaminase-Activated Prodrug of 2′,3′-Dideoxyinosine in the Mesenteric Vein Cannulated Rat Ileum

“…[7][8][9][10][11] Efficient targeting of dideoxynucleosides to the CNS via the prodrug approach requires a favorable rate of bioconversion to the parent drug within the target tissue. Among the brain tissue enzymes which have been successfully exploited for this purpose are those involved in the purine salvage pathway, including adenosine deaminase (ADA) [12][13][14][15][16] and xanthine oxidase. 17 For example, 6-chloro-2′,3′dideoxypurine (6-Cl-ddP) provided 10-fold higher concentrations of 2′,3′-dideoxyinosine (ddI) in the brain parenchyma of rats compared to ddI controls after intravenous infusions due to its increased lipophilicity and selective bioconversion to ddI by ADA present in the CNS.…”

Optimization of the Local Inhibition of Intestinal Adenosine Deaminase (ADA) by eryfftro-9-(2-Hydroxy-3-nonyl)adenine: Enhanced Oral Delivery of an ADA-Activated Prodrug for Anti-HIV Therapy

“…Several recent studies in these laboratories and elsewhere have explored the utility of adenosine deaminase (ADA) activated prodrugs for improving the delivery of dideoxynucleoside reverse transcriptase inhibitors to the central nervous system for the treatment of AIDS dementia complex. [1][2][3][4][5][6] For example, 6-chloro-2′,3′-dideoxypurine (6-Cl-ddP), a blood-brain barrier activated prodrug of 2′,3′dideoxyinosine (ddI), increases the steady-state brain parenchyma/plasma concentration ratio of ddI by 10-fold due to its higher lipophilicity combined with selective bioconversion by ADA in the brain tissue. 2,7 A significant problem associated with the use of ADAactivated prodrugs and a potential concern for any target tissue activated prodrug is the low oral bioavailability of the prodrug due to presystemic bioconversion to drug by enzymes present in the intestinal wall.…”