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1592U89, a Novel Carbocyclic Nucleoside Analog with Potent, Selective Anti-Human Immunodeficiency Virus Activity SUSAN M

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1592U89, a Novel Carbocyclic Nucleoside Analog with Potent, Selective Anti-Human Immunodeficiency Virus Activity SUSAN M ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1997, p. 1082–1093 Vol. 41, No. 5 0066-4804/97/$04.0010 Copyright © 1997, American Society for Microbiology 1592U89, a Novel Carbocyclic Nucleoside Analog with Potent, Selective Anti-Human Immunodeficiency Virus Activity SUSAN M. DALUGE,1* STEVEN S. GOOD,1 MICHAEL B. FALETTO,1† WAYNE H. MILLER,1 MARTY H. ST. CLAIR,1 LAWRENCE R. BOONE,1 MARGARET TISDALE,2 NIGEL R. PARRY,2 JOHN E. REARDON,1 RONNA E. DORNSIFE,1 1 1 DEVRON R. AVERETT, ‡ AND THOMAS A. KRENITSKY § Glaxo Wellcome Inc., Research Triangle Park, North Carolina 27709,1 and Glaxo Wellcome plc, Stevenage, Hertfordshire SG1 2NY, United Kingdom2 Received 23 August 1996/Returned for modification 5 November 1996/Accepted 26 February 1997 1592U89, (2)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol, is a car- bocyclic 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 mM for 1592U89 and 0.23 mM for AZT). 1592U89 showed minimal cross-resistance (approximately twofold) with AZT and other approved HIV reverse transcriptase (RT) inhibitors. 1592U89 was synergistic in combi- nation 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 CD41 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 (2)-carbovir (CBV). However, the in vivo pharmaco- kinetic, 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 a, b, g, and « 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 mM) 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. Nucleoside human immunodeficiency virus (HIV) reverse significant anti-HIV activity in the class of carbocyclic nucleo- transcriptase (RT) inhibitors continue to be the cornerstone of sides with the analog of 29,39-didehydro-29,39-ddA. The anti- AIDS therapy. Side effects limit the use of 39-azido-39-deoxy- HIV activity of the racemic guanine member of this 29,39- thymidine (AZT), 29,39-dideoxyinosine (ddI), 29,39-dideoxycy- unsaturated carbocyclic series, carbovir, was described by tidine (ddC), and 29,39-dideoxy-29,39-didehydrothymidine (d4T) Vince et al. (64). We synthesized the (2) enantiomer of car- (15, 36, 41, 49, 54, 67). In addition, resistance to single agents bovir (CBV) and its triphosphate (CBV-TP), studied the phos- has emerged in the clinic (25, 28, 65). For these reasons we phorylation of CBV by cellular enzymes (37), and verified the have continued to search for nucleoside analogs with greater selectivity of CBV-TP for HIV RT over cellular DNA poly- efficacy, less toxicity, and improved resistance profiles for use merases (13, 33). Although we confirmed its potent in vitro in rationally designed combination regimens. anti-HIV activity, we found CBV to be deficient in several Carbocyclic nucleosides, lacking the labile glycosidic linkage respects as an anti-HIV therapy. As with other guanines, in between heterocycle and sugar, could offer an attractive in vivo vivo toxicities seen with CBV in animals could, in part, be stability advantage over the 29,39-dideoxynucleosides. How- attributed to low aqueous solubility. Oral absorption of CBV ever, the carbocyclic versions of dideoxyadenosine (ddA), ddI, was found to be limited (26 and 23% oral bioavailability in the ddC, dideoxyguanosine, and dideoxyribosylthymine have dem- rat and monkey, respectively) (7), a finding consistent with onstrated minimal anti-HIV activity (38). We first detected published studies in the rat (2, 22). In addition, brain penetra- tion of CBV was inefficient relative to that of AZT (see below). We continued the synthesis and evaluation of a wide variety of * Corresponding author. Mailing address: Medicinal Chemistry Di- carbocyclic nucleosides containing the cyclopentenyl sugar vision, Glaxo Wellcome Inc., 5 Moore Dr., Research Triangle Park, mimic in search of a compound with a satisfactory preclinical NC 27709. Phone: (919) 483-2095. Fax: (919) 483-6053. E-mail: susan profile. [email protected]. We now report that 1592U89, (2)-(1S,4R)-4-[2-amino-6- † Present address: Pfizer Central Research, Groton, CT 06340. ‡ Present address: ICN Pharmaceuticals, Inc., Costa Mesa, CA (cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-metha- 92626. nol (Fig. 1), has properties, including a unique mechanism of § Present address: Krenitsky Pharmaceuticals Inc., Durham, NC activation, which allow it to correct for the deficiencies of CBV 27707. and prodrugs of CBV. In this and the following two papers (14, 1082 VOL. 41, 1997 ANTI-HIV AGENT 1592U89 1083 plaque assay (29). Previously described assays were used to measure activity against hepatitis B virus (HBV) (9, 24), human cytomegalovirus (HCMV) (16), and feline immunodeficiency virus (FIV) (48). Combinations of 1592U89 with other anti-HIV agents. The anti-HIV-1 activity of 1592U89 in combination with other inhibitors was assayed by an HIV cyto- pathic assay in MT4 cells where cytopathic effect was quantified using either the vital dye 3-[4,5-dimethylthiazol-yl]-2,5-diphenyltetrazolium bromide (MTT) or the DNA stain propidium iodide. The 50% inhibitory concentrations (IC50s) were calculated from the percent cytoprotection for each compound alone and for each compound in the presence of multiple concentrations of the other FIG. 1. Structure of 1592U89 (compound 1). compound. Combination IC50s were converted to fractional inhibition concen- trations (FIC50) by dividing the concentration of each compound in the combi- nation by its IC50 when acting alone. Isobolograms were generated by plotting the FIC50s of one compound versus the corresponding values for the second 58), we have summarized our understanding of the manner in member of each combination. which the 6-cyclopropylamino modification in 1592U89 results Urinary recovery of CBV in rats given oral 1592U89, CBV, and analogs. in its unique biological profile. Compounds were dissolved in water with the addition of small amounts (equimo- lar or less) of hydrochloric acid or sodium hydroxide, as required, and adminis- (This work was presented in part at the 34th Interscience tered to male CD rats (Charles River Laboratories, Wilmington, Mass.) weighing Conference on Antimicrobial Agents and Chemotherapy, Or- 285 to 390 g (n 5 3 per compound) by intragastric intubation. Doses were lando, Fla., 4 to 7 October 1994 [3, 7, 13, 19] and at the Eighth equivalent, on a molar basis, to 10 mg of CBV per kg of body weight. Urine was International Conference on Antiviral Research, Santa Fe, collected for 24 h and analyzed for CBV content by HPLC using a C18 Microsorb MV column (250 by 4.6 mm [inside diameter]; Rainin Instrument Co., Woburn, N.Mex., 23 to 28 April 1995 [6, 18]. Clinical evaluation of Mass.) eluted isocratically at 1 ml/min with a mobile phase of 6% methanol and 1592U89 in HIV-infected patients has begun.) 6% acetonitrile buffered to pH 7.0 with 25 mM ammonium phosphate containing 0.3% TEA. The retention time for CBV was about 10 min. The column was purged with 60% acetonitrile in the phosphate-TEA buffer for 4 min and re- MATERIALS AND METHODS equilibrated to initial conditions for 10 min between each analysis. The UV Materials. 1592U89 (compound 1), CBV (compound 2), and related chiral absorbance of the column eluate was monitored at 260 nm, and CBV concen- carbocyclic nucleosides in Table 1 were synthesized at Glaxo Wellcome Inc. from trations were determined by comparison to a calibration curve prepared with the corresponding 6-chloropurine (compound 4) (5, 5a, 5b). All carbocyclic normal urine. nucleosides used were enantiomerically pure and have the same absolute con- Pharmacokinetics and disposition of 1592U89, CBV, and analogs in the rat. figuration as that of CBV. AZT, ddI, ddC, d4T, (2)-(29R,59S)-1-[2-(hydroxy- Compounds were dissolved in normal saline with the addition of small amounts methyl)-1,3-oxathiolan-5-yl]cytosine (3TC), nevirapine, and (3S)-tetrahydro-3- (equimolar or less) of hydrochloric acid or sodium hydroxide, as required, and furyl N[(1S,2R)-3-(4-amino-N-isobutylbenzenesulfonamido)-1-benzyl-2-hy- administered to male CD rats (230 to 360 g) by bolus injection into the tail vein droxypropl]carbamate (141W94) were synthesized at Glaxo Wellcome Inc. or by intragastric intubation (n 5 3 per compound per dose route). Serial blood [8-3H]dATP and [8-3H]dGTP used for DNA polymerase assays were from Du- samples were obtained from each rat via jugular vein cannulas according to the pont-New England Nuclear. [8-3H]1592U89 and [8-3H]CBV were radiolabelled method described by Upton (62).
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