1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity

Abstract

1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, is a carbocyclic nucleoside with a unique biological profile giving potent, selective anti-human immunodeficiency virus (HIV) activity. 1592U89 was selected after evaluation of a wide variety of analogs containing a cyclopentene substitution for the 2'-deoxyriboside of natural deoxynucleosides, optimizing in vitro anti-HIV potency, oral bioavailability, and central nervous system (CNS) penetration. 1592U89 was equivalent in potency to 3'-azido-3'-deoxythymidine (AZT) in human peripheral blood lymphocyte (PBL) cultures against clinical isolates of HIV type 1 (HIV-1) from antiretroviral drug-naive patients (average 50% inhibitory concentration [IC50], 0.26 microM for 1592U89 and 0.23 microM for AZT). 1592U89 showed minimal cross-resistance (approximately twofold) with AZT and other approved HIV reverse transcriptase (RT) inhibitors. 1592U89 was synergistic in combination with AZT, the nonnucleoside RT inhibitor nevirapine, and the protease inhibitor 141W94 in MT4 cells against HIV-1 (IIIB). 1592U89 was anabolized intracellularly to its 5'-monophosphate in CD4+ CEM cells and in PBLs, but the di- and triphosphates of 1592U89 were not detected. The only triphosphate found in cells incubated with 1592U89 was that of the guanine analog (-)-carbovir (CBV). However, the in vivo pharmacokinetic, distribution, and toxicological profiles of 1592U89 were distinct from and improved over those of CBV, probably because CBV itself was not appreciably formed from 1592U89 in cells or animals (<2%). The 5'-triphosphate of CBV was a potent, selective inhibitor of HIV-1 RT, with Ki values for DNA polymerases (alpha, beta, gamma, and epsilon which were 90-, 2,900-, 1,200-, and 1,900-fold greater, respectively, than for RT (Ki, 21 nM). 1592U89 was relatively nontoxic to human bone marrow progenitors erythroid burst-forming unit and granulocyte-macrophage CFU (IC50s, 110 microM) and human leukemic and liver tumor cell lines. 1592U89 had excellent oral bioavailability (105% in the rat) and penetrated the CNS (rat brain and monkey cerebrospinal fluid) as well as AZT. Having demonstrated an excellent preclinical profile, 1592U89 has progressed to clinical evaluation in HIV-infected patients.

Tautomerism in drug discovery

“…Drugs with potential NH to N tautomerism include those used for the treatment of HIV 15 [34,35], 16 [36], epilepsy (17) [37], and skin (18) [38,39], lung and pancreatic cancers (19) [40][41][42]. They all involve amine (NH 2 or NH) to imine tautomerism a change that decreases the aromaticity of each heteroaromatic system.…”

Recent advances in the synthesis of fluorinated nucleosides

“…In addition, the fluorinated cyclopentenyladenine 526 238 and 5 0 -substituted fluoroneplanocin A analogues 527 239 were also prepared and biologically evaluated by this group. 246,247 have been regarded as the most interesting therapeutic candidates for anti-HIV therapy, because of their potent antiviral activities. Introduction of a fluorine atom at the 2 0 -position of dideoxypurine nucleosides is well known to stabilize the glycosyl bond.…”

Synthesis of new 6-substituted purinyl-5′-nor-1′-homocarbanucleosides based on indanol

“…This modification endows them with greater biostability than nucleosides by making them more resistant to the hydrolytic action of phosphorylases. 3,4 The anti-AIDS drug carbovir (I), 5 which selectively inhibits HIV reverse transcriptase, and its equally potent but less toxic analogue abacavir (II), 6 are cyclopentenyl nucleosides CANs in which the sugar ring of natural nucleosides has been replaced with a cyclopentene ring. Variants of carbocyclic nucleosides include 1 0 -homonucleosides, in which further resistance to enzymatic degradation has been sought by insertion of a methylene group between the heterocyclic base and C-1 of the pseudosugar moiety 7 and a number of norcompounds in which and improved selectivity index has been achieved by substituting an hydroxyl group for a pseudosugar hydroxymethyl (e.g., the hydroxymethyls on C-5 0 of aristeromycin 8 and C-3 0 of carbocyclic oxetanocin analogues 9 ).…”