Adenosine deaminase inhibitors

Use adenosine deaminase inhibitor (for hairy cell leucemia treatment)... 

The SET-induced rearrangement of phenylallylphosphites developed by Ben-trude et al. [43, 44] was used for the synthesis of new nucleotides bearing phosphonate moieties (Scheme 18) [40,50,51], which are active against HIV [52] and act as adenosine deaminase inhibitors [53]. 

The susceptibilities of some of these fluorinated purine nucleosides to the action of enzymes are now described. In contrast to the inertness of the 2 -deoxy-2 -fluoro- and 3 -deoxy-3 -fluorocytidine analogs 739, 744, and 821 towards cytidine deaminase, the adenosine compounds 867, 883, and 906 are readily deaminated - by the adenosine deaminase in erythrocytes and calf intestine, but the resulting (deaminated) inosine compounds (from 867 and 883), as well as 888, are highly resistant - to cleavage by purine nucleoside phosphorylase (to give hypoxanthine base for the first two). The reason was discussed. Both 867 and 883 can form the 5 -triphosphates, without deamination, in human erythrocytes or murine sarcoma cells in the presence of 2 -deoxycoformycin, an adenosine deaminase inhibitor, but... 

T. brucei is unable to synthesize purines de novo and, as such, is dependent upon salvage mechanisms from the host. A number of transporters and enzymes are used by T. brucei to accomplish this task, and inhibition of these targets offers promise for development of trypanocides [39]. This strategy has been validated by demonstration that cordycepin (34), a substrate for T. brucei adenosine kinase (TbAK), which terminates RNA synthesis and parasite growth, can cure stage 2 HAT infections in mice when coadministered with deoxycoformycin (35), an adenosine deaminase inhibitor [40]. 

L. M. Hansen and P.A. Kollman, Free energy perturbation calculations on models of active sites Applications to adenosine deaminase inhibitors, J. Comp. Chem. 11 994 (1990). 

Figure 2. Adenosine deaminase inhibitors and tetrahedral intermediate 2.

V. Pragnacharyulu, A. Fox, and P. J. Marangos, Regulation of adenosine concentration and cytoprotective effects of novel reversible adenosine deaminase inhibitors, J. Pharmacol. Exp. Ther. 283 1230 (1997). 

The adenosine deaminase inhibitor pentostatin is a natural product derived from Streptomyces and structurally it resembles the transition state of adenosine as it is hydrolyzed by adenosine deaminase. 

Pentostatin is an adenosine deaminase inhibitor primarily used as an antineoplastic agent for lymphoid malignancies, and produces a profound lymphopenia. It is now frequently used for steroid-resistant graft-versus-host disease after allogeneic stem cell transplantation, as well as in preparative regimens prior to those transplants to provide severe immunosuppression to prevent allograft rejection. 

Adenosine deaminase catalyzes the hydrolytic deamination of adenosine and 2 -deoxyadenosine to inosine and 2 -deoxyinosine respectively. Inhibition of adenosine deaminase leads to an accumulation of its substrates which results in adenosine receptor-mediated effects. Most inhibitors are not reported to have antinociceptive properties, but 2 -deoxycoformycin was proven to have an inhibitory effect on pain transmission (Poon and Sawynok, 1999), and Fujisawa Pharmaceuticals claim adenosine deaminase inhibitors to be active against chronic pain. 

Poon, A., Sawynok, J. Antinociceptive and anti-inflammatory properties of an adenosine kinase inhibitor and an adenosine deaminase inhibitor, J. Eur. J. Pharmacol. 1999, 384, 123-138. 

Tsuji, K., Terasaka, T., Nakamura, K. (Fujisawa Pharmaceuticals Corporation, Ltd.) Imidazole compounds and their use as adenosine deaminase inhibitors, WO 0153271. 

Nosaka K, Takahashi T, Nishi T et al. (1997) An adenosine deaminase inhibitor prevents puromycin aminonucleoside nephrotoxicity. Free Rad Biol Med 22 597-605 Park Y-S, Guijarro C, Kim Y et al. (1998) Lovastatin reduces glomerular macrophage influx and expression of monocyte chemoattractant protein-1 mRNA in nephrotic rats. Am J Kidney Dis 31 190-194... 

Figure 4.3 Example of an activity cliff illustrated by closely related adenosine deaminase inhibitors having dramatic potency differences. The introduction of a hydroxyl group that coordinates a zinc cation in the active site of the enzyme adds several orders of magnitude to the potency of an inhibitor.

Normal PRP Blood was collected in presence of 2= eoxyoof mydn (adenosine deaminase inhibitor) and dilazep (adenosine transport inhibitor) to maintain steady-state levds of dasma adenosine. 

Terasaka, T., Kinoshita, T., Kuno, M., Nakanishi, I. A highly potent non-nucleoside adenosine deaminase inhibitor efficient drug discovery by intentional lead hydridization. J. Am. Chem. Soc. 2004, 126, 34-35. 

The synthetic potential of a novel precursor of 2,6-diaminopurine CDK inhibitors, 2-(benzylsulfanyl)-6-chloro-9-isopropylpurine, has been described <05EJO939>. Novel highly potent adenosine deaminase inhibitors containing the pyrazolo[3,4-c/]pyrimidine ring system have been reported <05JMC5162>. The synthesis of substituted 6-phenylpyrazolo[3,4-c/]pyrimidines as potential adenosine A(A2) receptor antagonists has been published... 

Omura, S. Imamura, N. Kuga, H. Ishikawa, H. Yamazaki, Y. Okano, K. Kimura, K. Takahashi, Y. Tanaka, H. Adechlorin, A New Adenosine Deaminase Inhibitor Containing Chlorine. Production, Isolation and Properties. J. Antibiot. 1985, 38, 1008-1015. 

Deoxycoformycin and cordycepin have been isolated from a new strain of Aspergillus nidulans Y176-2 cultured on wheat-bran, the first example of a potent adenosine deaminase inhibitor (2-deoxycoformycin) occurring in a fungus. ... 

D-glucose as the chiral starting material, the former being converted to a 4-amino-4-deoxy-D-mannose intermediate, the latter to a 3-amino-3-deoxy-D-mannose derivative. The adenosine deaminase inhibitor (+)-EHNA (60) has been prepared using L-ascorbic acid as the source of the chiral oxiran precursor (61). 

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