'534 IDrugs 1999 Vol 2 No 6
`
`XP-001083882
`Poster Highlights I
`Peter Robins
`
`Address
`Current Drugs Ltd
`Middlesex House
`34-42 Cleveland Street
`London
`W1P6LB
`UK
`Email: peterro@cursci.co.uk
`
`IDrugs 1999 2(6):534-537
`©Current Drugs Ltd ISSN 1369-7056
`
`A-176120
`Among the new drugs presented in the morning poster
`session on the first day of the AACR meeting was Abbott
`Laboratories' A-176120, an analog of famesyl pyrophosphate
`and an inhibitor of Ras famesyltransferase (Frase). The
`compound was discovered as part of an SAR program at
`Abbott to develop antihypercholesterolemic inhibitors of
`squalene synthase (SSase) without activity at Frase. Certain
`1,2-analogs of a series of cyclobutanes, such as A-87049,
`showed acceptable selectivity profiles, but this was reversed
`in 1,3-analogs, eg, A-87050, which were potent inhibitors of
`Frase, but weak inhibitors of SSase. When the alkyl groups
`of A-87050 were replaced with benzyl (eg, A-88681), SSase
`activity was virtually eliminated. Replacement of the
`cyclobutane moiety with benzene-1,2,4,5-tetracarboxylic acid
`led to A-122330 which was even more potent. Final
`modifications then led to A-176120, which showed IC50 =
`1.18 ± 0.3 nM for Frase (compared to 10,000 nM for SSase)
`the closely-related enzymes,
`and was selective over
`geranylgeranyltransferase I and ll (IC50 = 423 and 3000 nM,
`respectively). A-176120 also inhibited Ras processing in
`NIH3T3 H-Ras
`transformed cells and HCT116 K-Ras
`mutated cells with ED50 = 1.6 and 0.5 µM, respectively.
`
`3-IAABU
`Another poster described the cancericidal effects of the
`tubulin ligand, 3-(iodoacetamido)benzoylurea (3-IAABU),
`which has almost completed preclinical trials and is being
`prepared for phase I clinical trials by Mount Sinai School of
`Medicine, New York and the Kaplan Cancer Center, in
`collaboration with Pharmacia & Upjohn Inc. 3-IAABU was
`discovered via a screening program with Cytoskeleton Inc of
`Denver, Colorado, USA, and has shown activity in a range
`of cancer cell lines with IDw values in the range 0.015 to 0.29
`µM for leukemic cells and 0.06 to 0.92 µM for solid tumor
`cells. 3-IAABU also inhibits the growth of Daudi cells with
`or without expression of P-glycoprotein (Pgp), suggesting
`that it is not a substrate for Pgp and is therefore independent
`of MOR-related drug resistance.
`
`TAS-102
`5-Fluorothymidine (FrD) is effective against human tumors
`that are resistant to 5-FU, but is metabolized by thymidine
`to
`the
`inactive metabolite, 5-
`phosphorylase (TPase)
`fluorothymine. Taiho Pharmaceutical Co Ltd has developed
`TAS-102, a nucleoside-based antitumor therapy consisting of
`fTD and the TPase inhibitor (TPI), 5-chloro-6-(2-imino-
`
`P.D. -£~ .. ~-5 ..... : ............. C,'\
`) .. 2.1:/.:: .. f;.}1 ........ ~
`
`P.
`
`pyrrolidin-1-yl)methyl-2,4(1H,3H)pyrimidinedione hydrochlo(cid:173)
`ride, in a 1:0.5 ratio, which effectively prevents the biological
`functions of thymidine phosphorylase, such as angiogenesis
`and metastasis. Given the role of FrD as a substrate for
`TPase, the preclinical pharmacokinetics (PK) of TAS-102
`were of prime importance and species differences in the PK
`profiles were presented in a poster from Taisho. The
`monkey was exceptionally different from rat and dog,
`showing a higher concentration of FrD in the plasma and a
`slower elimination time. Since the inhibition rate of TPase
`digestion of FfD by TPI in human tissues was similar to that
`of monkey tissues, it is expected that TAS-102 will be
`effective in the clinical setting and the compound has now
`entered phase I clinical trials.
`
`PNU-214936
`Tumor-targeting Staphylococcal enterotoxin A (SEA)-Fab
`fusion proteins are potent T-cell activators which are being
`investigated by Pharmacia & Upjohn for breast and lung
`cancers. The first-generation SEA-fusion protein, PNU-
`214565 (r-C242Fab-SEA), reached phase I clinical trials but
`was discontinued due to systemic toxicities, such as fever
`and hypotension, at low doses. Toxicity was inversely
`correlated to baseline concentrations of plasma anti-SEA,
`which are unpredictable and widely variable. Development
`was superseded by a second-generation fusion protein,
`PNU-214936 (Fab5T4V13-SEAm9), which has a mutation at
`residue 227 of SEA that disrupts the MHC class II
`intermediate affinity zinc-bridge binding site and improves
`its
`therapeutic window. PNU-214936 may
`thus be
`administered at doses up to 32-fold greater than those used
`with PNU-214565. The new phase I clinical trial is designed
`so that no pair of individuals with equivalent baseline levels
`of anti-SEA will receive the same dose of drug.
`
`TAS-106
`A series of five posters from Taiho Pharmaceutical Co Ltd
`described the preclinical pharmacology and toxicology of
`the new TAs-106, a novel antitumor ribonucleoside, for
`the major cytotoxic mechanism appears to be
`which
`inhibition of RNA synthesis. The IC50 values of cell growth in
`culture were 0.033 and 0.035 µM, following exposure for 24
`and 72 h, respectively. Moreover, almost the sa~e IC50 (0.068
`µM) was obtained when cells were exposed to drug for 4 h
`on each of 3 days. The in vivo anti tumor activity of T AS-
`106 was assessed against human tumor xenografts in nude
`rats on three different dosage schedules in a 2-week
`dosing system. The doses selected were the minimum
`toxic doses on each of the schedules: 6 mg/kg/day once a
`week, 1 mg/kg/ day 3 times a week, and 0.3 mg/kg/ day 5
`times a week. The tumor growth inhibition rates (IRs) of
`TAS-106 for OCUM-2MD3 stomach tumors on the once a
`week, 3 times a week, and 5 times a week schedules were
`91.8, 89.2 and 90.8%, respectively, while the !Rs for LX-1
`lung tumors were 98.0, 90.6 and 83.5%, respectively.
`Schedule-independent antitumor efficacy was suggested
`to be a pharmacological characteristic of TAS-106, which is
`expected to begin clinical trials in the US in September.
`
`BNSDOCID: <XP __ 1083882A
`
`I >
`
`

`

`Meeting Report 90th AACR 535
`
`CHS-828
`Leo Pharmaceutical Products Ltd is developing the novel
`agent,
`CHS-828
`anti tumor
`cytotoxic
`(N-[6-(4-
`chlorophenoxy)hexyl]-N' -cyano-N"-4-pyridylguanidine), which
`was selected via a screening program based on human and
`rodent tumor cell lines. CHS-828 showed a different activity
`profile in ten different cell lines from known alkylating agents,
`topoisomerase inhibitors, antimetabolites and spindle poisons.
`Oral treatment with CHS-828 in non-toxic doses caused tumor
`growth arrest (100 mg/kg once daily) or tumor regression (250
`mg/kg once weekly) in MCF-7 tumor bearing mice. Mice with
`NYH small cell lung cancer xenografts were particularly
`sensitive to CH5-828, with a total regression of tumors at
`30 mg/kg once daily. Disease-free survival was observed after 4
`weeks treatment with 250 mg/kg once weekly .. Toxicity
`associated with high-dose CH5-828 consisted mainly of
`gastrointestinal disturbances and atrophy of lymphoid organs.
`CHS-828 is at present undergoing phase I clinical evaluation in
`three patients in Uppsala, in collaboration with the European
`Organization for Treatment of Cancer. Although the lowest
`dose is still being investigated, early indications are that the
`drug is well tolerated.
`
`PNU-166196
`Phannacia & Upjohn Inc is developing PNU-166196, a new cx(cid:173)
`bromoacryloyl derivative of distamycin A. It is a member of a
`novel class of DNA minor groove binders which displays
`potent cytotoxic activity in vitro on human and murine tumor
`cell lines and antitumor activity in vivo against experimental
`tumor models showing an outstandingly high therapeutic
`index. Pharmacia plans to begin phase I clinical trials with this
`compound in October or November 1999.
`
`CDDO
`From a series of some 200 analogs of oleannane triterpenoids,
`researchers at Dartmouth Medical School, NH, USA, have
`selected a nitrile derivative, 2-cyano-3,12-dioxoolean-l,9-dien-
`28-oic
`acid
`(CDDO), which
`shows promise
`as
`a
`chemopreventive agent. In particular, it effectively inhibits
`many leukemia cell lines at concentrations ranging from 0.001
`to 1 µM. In vitro work with LCDB leukemia cells is being carried
`out by J Letterio (National Cancer Institute, USA) who
`presented a separate poster that described the ability of the
`compound to induce cell differentiation. In vivo work with the
`compound is scheduled to start shortly, with a view to
`preparing the compound ultimately for human trials in
`myeloid leukemia.
`
`CCl-n9
`The sirolimus analog CCI-779 (or cell cycle inhibitor 779) was
`described in a poster from Wyeth-Ayerst Research. This has a
`very similar profile to rapamycin but has been developed as a
`superior iv formulation. Growth inhibitory effects were blocked
`by the FKBP inhibitory molecule ascomycin, suggesting that the
`mechanism of action of CCI-779 is similar to sirolimus. PDGF
`stimulation of the human glioblastoma line T98G was markedly
`inhibited (IC50 - 1 pM) by CCI-779 in serum free medium. In
`nude mouse xenografts,
`the growth of staged human
`glioblastoma (U87MG) tumors was blocked by a variety of
`dosing regimens, with a minimum effective dose of 0.1 to
`1.0 mg/kg. Staged tumors treated for 5 consecutive days with
`
`CCI-779 were still growth inhibited 14 days later. In contrast,
`the effect of the compound on immune function was lost as
`early as 1 day after drug withdrawal. Various histological
`tumor types (pancreas, breast, prostate) were also sensitive to
`CCI-779 in nude mouse xenografts. These data suggest that
`CCI-779 will be an effective antitumor agent for several human
`tumor types when given via an intermittent dosing regimen;
`the compound began phase I clinical trials at two sites in
`Europe and the US in the last quarter of 1998.
`
`NSC-609395 and NSC-639829
`SRI International of Menlo Park, CA, USA, presented a pair of
`posters describing preclinical toxicology studies with a pair of
`NCI
`compounds, halichondrin B
`(NSC-609395)
`and
`NSC-639829 (dimethylaminobenzoylphenylurea). The former is
`a structurally-unique tubulin-binding compound derived from
`extracts of Pacific sponge of the genus, Axinella which was
`cytotoxic in vivo in the murine P-388, B16 and L1210 models,
`and showed activity in preliminary data from in vivo models of
`human mel,moma, colon and ovarian solid tumor xenografts.
`However, development of the compound was terminated due
`to undisclosed problems, although work continues at the NCI
`to discover structural analogs that might prove more suitable.
`NSC-639829, on the other hand, has proceeded well through
`preclinical evaluation and work related to an IND application
`that is expected to be filed before the end of the year has begun.
`
`CEP-701
`Pancreatic ductal adenocarcinoma (PDAC) is highly refractory
`to available treatment regimens and associated with a poor
`survival rate. Cephalon Inc is developing a number of Trk
`tyrosine kinase inhibitors, including CEP-701 (Figure l}, which
`have shown excellent promise for the treatment of this disease.
`CEP-701 is selective for this enzyme and demonstrated the
`following IC50 values in preclinical assays of conventional
`protein tryosine kinase inhibitors: 2 nM (Trk); 65 nM (VEGFR);
`>10,000 nM (lnsR); >10,000 nM (EGFR}; and 43 nM (PKC).
`CEP-701 (100 nM) potently inhibits Trk in intact cells (75 to
`100%) and inhibited PDGFR by up to 100% in intact cells.
`CEP-751, the 0-methyl derivative of CEP-701, was in fact the
`lead compound from this program and an iv prodrug
`formulation completed phase
`I clinical
`trials, but
`its
`development has been put on hold as a result of particularly
`positive results from phase I trials of CEP-701. An oral
`formulation of the latter compound has now completed phase I
`trials in normal volunteers. Phase II trials in prostate cancer are
`expected to begin in the US before the end of 1m and will
`include an arm in pancreas cancer in gemcitabine-treated and -
`naive patients.
`
`Onconase
`Alfacell Corp is developing Onconase, a novel amphibian
`ribonuclease with a broad-spectrum of antitumor activity that is
`currently in phase Ill trials for malignant mesothelioma. Based
`on previously observed in vitro synergisms between Onconase
`and doxorubicin (DOX) against MDA-MB-231 breast cancer
`cells, the company conducted studies with Onconase and OOX
`as single agents and in combination in two in vivo models in
`nude mice: a flank model (tumor cells administered sc); and a
`systemic lung metastatic and survival model (tumor cells
`administered iv). In both flank and systemic models, Onconase
`
`BNSDOCID: <XP __ 1083882A_I_>
`
`

`

`536 !Drugs 1999 Vol 2 No 6
`
`was used at 25 mg/kg dose ip twice a week for 3 weeks, and
`DOX at 3 or 5 mg/kg on the same schedule iv. Systemic
`treatments started 3 days after tumor inoculation. The
`combination had a significantly greater effect than either agent
`alone, resulting in a decrease of tumor size (flank) and number
`of metastatic foci (systemic). It also had a significantly greater
`effect on prolongation of survival time, with median survival
`times of 58, 72, 76 and 187 days for control, Onconase, DOX
`(5 mg/kg) and Onconase + OOX (5 mg/kg), respectively. The
`increased life span for the last group was 222%, of which 30%
`were long-term survivors. In the ongoing study, the beneficial
`effed of the combination of ONC+DOX on survival in mice has
`been confirmed with a lower dose of DOX (3 mg/kg).
`Onconase has already been tested as a single agent in a
`preliminary, broad-eligibility phase Il trial involving 17 patients
`with breast cancer, and demonstrated highly favorable results
`that the company ultimately hopes to use as a basis for phase III
`trials, although it is concentrating resources on the phase ill
`trials in mesothelioma.
`
`A-1n430
`The matrix metalloproteinase (MMP) family is implicated in the
`progression of several malignancies including prostate cancer.
`A poster from Abbott Laboratories described the ability of a
`new macrocyclic MMP inhibitor, A-177430, to block tumor
`growth and metastases in a syngeneic model of rat prostate
`cancer. A-177430 is highly potent in substrate assays in vitro
`against a number of different MMPs, including fibroblast
`collagenase (MMP-1; IC50 = 1.8 nM); gelatinase-A (MMP-2; IC50
`= 22 nM); gelatinase-B (MMP-9; IC50 = 5.6 nM); stromelysin
`(MMP-3; IC.O = 3.9 nM) and matrilysiri (MMP-2; IC50 = 1.6 nM).
`In in vivo studies, male Copenhagen rats were inoculated with
`Mat Ly Lu rat prostate cancer cells (1 x 10(6) cells sc) and
`administered A-177430 (10 to 100 mg/kg/day ip) for 16 days.
`The compound produced a do~ependent decrease in tumor
`volume compared to control, most significantly in the lungs,
`where no evidence of metastatic tumor metastases was
`observed after treatment with the maximum dose.
`
`NSC-691236 and NSC-691237
`A pair of posters from the National Cancer Institute (NCI)
`described the pharmacokinetics and toxicity in cynomolgus
`monkeys of two Pseudomonas exotoxin monoclonal antibody
`conjugates. LMB-9 (83ds(Fv)-PF38; NSC-691236) is a disulfide(cid:173)
`stabilized form of LMB-7, a single chain immunotoxin cytotoxic
`to I..ey antigen-bearing tumor cells, while B122 (RFB4 ds(Fv)(cid:173)
`PF38; NSC-691237) is toxic for CD22+ cells and exlubits
`in nude mice bearing human B-cell
`antitumor activity
`lymphomas. LMB-9 was eliminated biexponentially from
`plasma with a haH-life of 86 to 94 minutes; peak plasma levels
`were 0.61 and 7.69 µg/ml in monkeys treated with 0.1 mg/kg
`or 1.0 mg/kg, respectively. Leukocytosis occurred in all dose
`groups and one animal showed marked gastric ulceration and
`slight
`renal
`tubular necrosis upon histopathological
`examination. Administration of the second antibody conjugate,
`B122 (0, 0.1, 1.0, 125, 1.75, and 2.0 mg/kg iv qd every other
`day) produced lethargy and non dose-related leukocytosis in all
`dose groups. No significant changes were noted in the
`percentage of mononuclear cell populations positive for CD20
`or CD22. Elevated heart rate and mean arterial pressure
`occurred at 2.0 mg/kg/dose. Plasma levels ranged from 2.5 to
`53 µg/ml (0.1 to 2.0 mg/kg/dose) 10 minutes post-dose. It is
`
`hoped that both LMB-9 and BL22 will enter clinical trials at
`some point, although it is not clear when this might occur.
`
`TSP-1 analogs
`Taffy Williams, President and CEO of lnKine Pharmaceuticals
`the
`Co Inc (PA, USA), presented a poster describing
`antimetastatic activity of thrombospondin type 1 (fSP-1) repeat
`peptides, Cys-Ser-Val-Thr-Cys-Gly, and their analogs in both in
`vitro and in vivo assays. These peptides inhibited TSP-1-
`dependent in vitro tumor cell adhesion and invasion in a dose(cid:173)
`range of 50 to 300 µg/ml, while experimental melanoma tumor
`cell metastasis was inhibited by 50 to 90% in mice treated with
`peptide in a dose range of 0.01 to 1.0 mg/mouse administered
`either iv or ip. Scrambled peptide controls had no effect.
`Inhibition of metastasis was detected immediately after tumor
`implantation and 24 to 72 h later, suggesting that the peptide
`not only blocks initial tumor arrest but also subsequent tumor
`development. An undisclosed lead peptide has been identified,
`which will shortly undergo toxicological studies; it is expected
`to enter phase I clinical trials before the end of 1999. The work
`has also led to the identification of compounds potentially
`useful as imaging agents, these too are expected to commence
`clinical trials in 1999, although corporate partners are being
`sought for this aspect of the program.
`
`Tomatoes
`While virtually all other foodstuffs seem to have their 15
`minutes as potential carcinogens, new medical research
`suggests that the consumption of tomatoes, or more specifically
`lycopene, the carotenoid that gives them their colour, may
`actually prevent some forms of cancer. The Barbara Ann
`Karmanos Cancer Institute presented results from a study in
`prostate cancer patients with Lyc-0-Mato, a formulation of
`lycopene
`from Lycored Natural Products Ind Ltd in Beer(cid:173)
`Sheva, Israel. A total of 21 men with localized prostate cancer,
`scheduled for radical prostatectomy were rando!Tlly assigned to
`receive either Lyc-0-Mato (15 mg po bid) or no intervention for
`three weeks prior to surgery. Serum and tissue lycopene levels
`increased significantly in the intervention group, while levels of
`prostate-specific antigen declined significantly over three weeks
`in the same group. Within the treated group, 8 of 12 patients
`(67%) had organ-confined prostate cancer and 84% had tumors
`~ 4 cm3
`, compared to 44% and 55%, respectively, in the control
`group. The expression of biomarkers of proliferation decreased,
`whereas the markers of differentiation and apoptosis increased
`in the intervention group.
`
`·,
`
`MR1(scFv)
`A single-chain antibody fragment, MRl(scFv), with specific
`binding to tumor-associated EGFRvIII has been developed by
`Duke University Medical Center in collaboration with the
`Ottawa Regional Cancer Centre and the National Cancer
`Institute (NCI). A poster described work with [~]-radiolabeled
`MRl(scFv) which has been used to demonstrate specific and
`high-level targeting of xenografts. The affinity KA of MRl(scFv)
`for EGFRvIIl by BIAcore analysis was 4.3 x lff' M, and by
`Scatchard analysis was 1.0 x lff" M. Specificity of MRl(scFv) for
`EGFRvIII was demonstrated in vitro by incubating radiolabeled
`MRl (scFv) with the U87MG. ~GFR cell line in the presence or
`absence of competing unlabeled MRl(scFv). In biodistribution
`studies using athymic mice bearing sc U87MG ~GFR tumor
`
`BNSDOCID: <XP __ 1083882A_I_>
`
`

`

`intratumoral
`received paired-label
`xenografts,
`animals
`infusions of [12>l]SIPC-MRl (scFv) and (131IJSIPC-anti-Tac(scFv) as
`a control. MRl(scFv) demonstrated a high tumor uptake of 85%
`(1 h) and 16% (24 h) injected dose/g following administration.
`Specific/control scFv tumor uptake ratios of more than 20:1
`demonstrated specific localization of MRl(scFv). The excellent
`tumor retention of MRl(scFv) combined with its rapid
`clearance from normal tissues results in high tumor-to-normal
`organ ratios. It is hoped that the antibody fragment, or a similar
`example, will enter phase I clinical bials by the end of 1999.
`
`R-101933
`.<\ series of four posters from Janssen Pharmaceutica NV
`described the ability of a new, oral, imidazo.benzazepine P(cid:173)
`glycoprotein (Pgp) antagonist, R-101933 (Figure 1) to modulate
`multidrug
`resistance
`(MOR) without
`altering
`the
`pharmacokinetics of a co-administered drug. R-101933
`concentration-dependently restored the antiproliferative effect
`of anthracyclines, taxanes and vinca alkaloids
`in Pgp(cid:173)
`overexpressing
`1<562
`human
`leukemia
`cells, while
`demonstrating complete reversal of the sensitivity level of the
`non-resistant, Pgp-negative 1<562 cells at 3 mM. Complete
`reversal of the uptake and restoration of the intracellular
`disbibution of daunorubicin to the nucleus was also observed
`with R-101933 or S-9788 (10 mM; Servier) but not with
`verapamil. R-101933 appears to act not as a Pgp substrate but
`rather a Pgp antagonist. Furthermore, in photoaffinity labeling
`experiments with [3H]azidopine, R-101933
`inhibited Pgp
`labeling with IC50 = 0.84 µM, making it over hundred-fold more
`active than verapamil (IC50 = 110 µM). Oral treatment with
`R-101933 restores the sensitivity towards paclitaxel and
`adriamycin in resistant human tumors xenografted in athymic
`mice. Phase I bials of the compound began in The Netherlands
`in 1998, in which the compound has shown no significant
`alteration of the pharmac:okinetics or pharmacodynamis of
`paclitaxel or docetaxel in patients.
`
`T-138067
`Tularik Inc has discovered and optimiz.ed a novel class of
`cytotoxic pentafluorobenzenesulfonamides with
`efficacy
`Fi ure 1.
`
`Meeting Report 90th AACR 537
`
`against cell lines that express the MOR phenotype. These
`new agents are active against a broad variety of cell lines
`from breast, colon, ovarian, renal, lung, CNS and prostate
`tumors, and melanoma; for instance, the lead compound,·
`T-138067 (Figure 1), demonstrates the following IC50 values
`(µM): 0.05 (MCF-7); 0.034 (CCRF-CEM); 0.025 (OC-3F); and,
`0.06 (P388). A poster from the company described the SAR
`leading to this compound, which is currently undergoing
`phase I clinical trials that have yet to reach the maximum
`tolerated dose. Electron donating groups in the 4-position of
`aryl substituents on the sulfonamide were optimal for
`potency. Small alkoxy substituents were preferred, with
`maximum activity observed with methoxy. Aniline-derived
`sulfonamides were also preferred, compared to those
`derived from benzylamine or phenethylamine, while
`inversion of the sulfonamide resulted in effectively complete
`loss of activity. Secondary sulfonamides were optimal.
`
`TER-286
`Telik Inc is investigating the tumor-associated glutathione-5-
`transferase isotype Pl-1 (GSfPl-1) as the target for a number
`of potential anticancer treatments. A pair of posters at this
`conference reported work with the GSfPl-1 inhibitor, TER-
`199 (Figure 1), and its de-esterified analog, TER-117, which
`are effective inhibitors of MRP-1-mediated drug resistance.
`The program with GSfPl-1 has led to TER-286, a novel
`nitrogen mustard prodrug which was reported in a separate
`poster. This is not an inhibitor of GSTPl-1, but requires
`activation by the enzyme so employs a quite different
`strategy from TER-199 and analogs. In mouse embryo
`fibroblasts made from wild-type (wt) and GSTP1-1 knockout
`mice, the latter exhibited 2-fold greater resistance to TER-286
`compared to the wt (96.0 ± 20.0 µM compared to 177.5 ±
`42.0 µM). Thus tumors expressing high levels of GSfPl-1
`will be more sensitive to the cytotoxic effect of the drug. The
`drug has been selected as the first clinical candidate from the
`program and is scheduled to begin phase I clinical trials at
`the beginning of 2000.
`
`H
`
`~ H,C ,,'J(o-y
`
`HO~
`OH
`
`CEP-701
`(Cephalon)
`
`T-138067
`(Tutarik)
`
`R-101933
`(Janssen)
`
`TER-199
`(Tellk)
`
`;.•· ... ~
`BNSDOCID: <XP_· _··. __ 1083fi~2A_I_;·
`
`