EP1343434A1 - Procede d'administration conjuguee de levamisole et de 5-fluorouracile - Google Patents

Procede d'administration conjuguee de levamisole et de 5-fluorouracile

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Publication number
EP1343434A1
EP1343434A1 EP01995344A EP01995344A EP1343434A1 EP 1343434 A1 EP1343434 A1 EP 1343434A1 EP 01995344 A EP01995344 A EP 01995344A EP 01995344 A EP01995344 A EP 01995344A EP 1343434 A1 EP1343434 A1 EP 1343434A1
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European Patent Office
Prior art keywords
cancer
levamisole
fluorouracil
drug
group
Prior art date
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Application number
EP01995344A
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German (de)
English (en)
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EP1343434A4 (fr
Inventor
Seth Lederman
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Targent Inc
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Targent Inc
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Publication of EP1343434A1 publication Critical patent/EP1343434A1/fr
Publication of EP1343434A4 publication Critical patent/EP1343434A4/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to the field of pharmaceuticals, and to the field of cancer chemotherapy in particular. Specifically, the invention relates to methods of contemporaneously co-administering the drug levamisole, or its analogues, with 5-fluorouracil or related drugs, in order to treat patients afflicted with cancer.
  • Levamisole was originally developed and marketed as a racemic mixture, as the anmelmintic drug tetramisole (D. Thienpont et al, 1966, Nature 209:1084). Most of this activity was subsequently found to reside in the levorotary isomer, levamisole (I):
  • This protocol referred to herein as the "immunomodulatory levamisole regimen,” called for a 50 mg oral dose of levamisole, taken three times a day, for three days. This three-day regimen was repeated every other week throughout the course of therapy, which typically ranged from six months to two years in length.
  • This early work has been reviewed: P. Janssen, 1976, Progress Drug Res. 20:347-383; W. K. Amery, 1977, Cancer Treatment Reviews 4:167-194. Because cancer has been viewed as a defect of immune surveillance, and because levamisole was thought to have immunomodulatory properties, some experimental work began to evaluate whether levamisole would be useful in stimulating the immune system of cancer patients.
  • Adjuvant therapy with the combination of 5-FU and levamisole became accepted as a standard post-surgical regimen for Dukes' C, stage III colon cancer patients in the United States (NIH Consensus Conference: Adjuvant therapy for patients with colon and rectal cancer, 1990, . Am. Med. Assoc. 264: 1444- 1450).
  • the dosing schedule for levamisole was adapted directly from the regimen used for anmelmintic treatment, and was selected on the basis that immunomodulation by levamisole was the desired effect. Because levamisole was already available in an oral tablet formulation, oral dosing was adopted as the standard method of administration. In addition, the standard immunomodulatory regimen of levamisole was used.
  • a typical protocol is 50 mg levamisole, given orally every eight hours (t.i.d.) for three consecutive days (x 3 days), the three-day administration being repeated every two weeks (q.o.w.).
  • superimposed on this schedule are five daily infusions of 5-FU (450 mg/m 2 ) for the first five days, followed four weeks later by weekly infusions.
  • This regimen is continued for one year (C. Moertel, 1995, Ann. Intern. Med. 122: 321-326).
  • administration of both drugs on the same day was a rare and incidental occurrence.
  • 5-FU regimens alone are ineffective against many cancers, including colorectal cancer.
  • 5-FU has been used with some success as a cancer chemotherapy, either primary or adjuvant, for anal cancer, colorectal cancer, biliary tract cancer, carcinoid tumors, cervical cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatoblastoma, liver cancer, pancreatic cancer, prostate cancer, breast cancer and lung cancer.
  • 5-FU inhibits thymidylate synthetase, an enzyme required for DNA synthesis, and tumor cells that exhibit high levels of thymidylate synthetase seem to be more sensitive to 5-FU, but there are other possible mechanisms of action.
  • 5-FU is preferentially metabolized in tumor cells into 5-FdUTP, a pseudobase that can be incorporated into DNA, and 5-FUTP which can be incorporated into RNA.
  • 5-FU also induces apoptosis in cultured salivary gland culture cells by suppressing NF- ⁇ B activity (K. Aota et al, 2000, Biochem. Biophys. Res. Commun.
  • 5-FU should be considered as two different drugs, depending on the dosing regimen (A. Sobrero et ⁇ t, 1997, /. Clin. Oncol. 15:368-381).
  • the mechanism by which the immunomodulatory regimen of levamisole exhibits synergy with the antineoplastic activity of 5-FU has not yet been determined.
  • Some studies have examined whether pharmacological interactions between the two drugs may account for the clinical effects observed in trials where levamisole and 5-FU regimens have been superimposed. For example, one study examined whether levamisole and 5-FU interacted pharmacologically to inhibit growth in cultured tumor cell lines.
  • levamisole and 5-FU were studied on the in vitro colony formation of tumor cell lines.
  • certain cell lines A549 lung carcinoma cell line, A375 melanoma cell line
  • COLO205 colon carcinoma cell line and MCF7 breast carcinoma cell line did not.
  • these studies showed that very high doses of levamisole decreased the number of colonies in the presence of 5-FU but not in the presence of the 5-FU metabolite 5-fluorodeoxyuridine.
  • levamisole may be able to inhibit intracellular phosphatases and thereby lead to an increased cellular retention of FdUMP (fluorodeoxyuridine monophosphate, the active metabolite of 5-FU).
  • FdUMP fluorodeoxyuridine monophosphate
  • concentrations of serum levamisole achieved in vivo upon oral aclministration are far lower than the concentrations that inhibit phosphatases (J. Kovach et al, 1990, Proc. Am. Assoc. Cancer Res. 31:399, abst. 2365).
  • levamisole Certain of the pharmacologic effects of levamisole are associated with compounds of the general structural class to which levamisole belongs, and are not specific to levamisole alone.
  • the 4-hydroxy and 4-bromo analogues of levamisole are also capable of inhibiting phosphatases (J. Kovach et al, 1992, J. Natl Cancer Inst. 84:515-519).
  • Dexamisole the enantiomer of levamisole, is less active in potentiating the antineoplastic effect of BCNU against bladder cancer in rats (T. Hozumi, 1978, Gann 69:339-343).
  • IV aclministration has of course been a means of introducing levamisole to animals in the laboratory, but this route of aclministration has been associated with cardiac side-effects in at least two species: in rats cardiotoxicity was observed at IV doses as low as 2 mg/kg (G. Onuaguluchi, I. Igbo, 1990, Arch. Int. Pharmacodyn. 305:55-62), and ECG irregularities were seen in guinea pigs at 10 mg/kg IV (G. Onuaguluchi, I. Igbo, 1990, Afr. J. Med. Sci. 19:307-312). The effects are seen within 60 seconds of administration, and appear to be associated with the high transient concentrations that accompany a bolus injection.
  • parenteral administration of levamisole contemporaneously with parenteral 5-FU has not been considered or even conceived by those skilled in the art. This may be due to a combination of factors, which includes the cardiotoxicity associated with bolus IV administration in some species, the convenience and availability of oral dose formulations, and the cost and inconvenience of preparing an IV infusion in the absence of a commercially available parenteral formulation.
  • the notion that high hepatic concentrations of levamisole, generated by rapid oral absorption, are needed for activity would also discourage attempts at parenteral administration.
  • leucovorin is a substitute for levamisole in the therapeutic sense it is not equivalent in a mechanistic sense.
  • Levamisole and leucovorin are both effective as potentiators of 5-FU in adjuvant therapy, at least for Dukes' B or C colorectal cancer (N. Wolmark et al, 1999, J. Clin. Oncol. 17:3553-3559), therefore any improvement in the method of co-administration of levamisole and 5-FU would provide a superior drug regimen for adjuvant chemotherapy in the treatment of these conditions.
  • 5-FU with levamisole would offer some benefit when administered prophylactically to a subject exhibiting Bcl-2 overexpression in a pre-cancerous biopsy specimen, or exhibiting any other chromosomal marker or altered gene which might be found to correlate with outcome of adjuvant chemotherapy.
  • irinotecan (a topoisomerase I inhibitor) has been shown to be a useful salvage therapy for leucovorin/5-FU treatment failures.
  • irinotecan was administered in conjunction with leucovorin-5-FU therapy, and some benefit of triple therapy was demonstrated (L. Saltz et al, 2000, N. Engl. J. Med. 343:905-914).
  • Ethynyluracil (eniluracil) also potentiates the cytotoxic effects of 5-FU, by inhibiting dihydropyrimidine phosphate dehydrogenase (D Baccanari et al, 1993, Proc. Natl. Acad. Sci. U S A. 90:11064- 11068). Addition of levamisole to any of these drug combinations is expected to provide a beneficial effect.
  • the drug capecitabine (XelodaTM) is an orally available prodrug of 5-FU that is activated by enzymes that are particularly prevalent in liver and tumor cells. For this reason it may be given in higher doses than 5-FU itself, and is believed to produce higher concentrations of 5-FU in the tumor tissue. It is currently approved for treatment of refractory breast cancer. Preclinical studies show that capecitabine has significant activity against a variety of tumor types when used as monotherapy and in combination with other chemotherapeutic agents (R. Schilsky, 2000, Oncology (Huntingt.) 14:1297-1306; 1309-1311).
  • capecitabine is a 5-FU prodrug
  • levamisole would potentiate the activity of capecitabine, or of various other analogues or prodrags of 5-FU that are currently in development, such as for example doxifluridine and ftorafur (tegafur).
  • CMF cyclophosphamide, methotrexate, and fluorouracil
  • CAF cyclophosphamide, epirubicin, and fiuorouracil
  • CAF cyclophosphamide, AdriamycinTM (doxorubicin), and fluorouracil
  • An oral levamisole regimen has been superimposed on the CAF regimen in one trial with modest effects over untreated historical controls and no advantage over historical BCG immunotherapy controls (G. Hortobagyi et al, 1979, Cancer 43:1112-1122). The benefits of added levamisole obtained by Hortobayagi e* ⁇ /.
  • levamisole and 5-FU being consistently simultaneously present in humans appears to have occurred in a pharmacokinetic and toxicologic investigation of high-dose levamisole (Reid et al, 1998, Cancer Chemother. Pharmacol. 41:477-484).
  • patients with advanced, inoperable cancers were dosed with 5-FU daily for five days, and levamisole was given orally 3 times a day for the same five days, with the morning dose given prior to the 5-FU injection. This was repeated every five weeks, with increasing doses of levamisole, up to doses of 300 mg/m 2 t.i.d.
  • the maximum tolerable dose was found to be 100 mg/m 2 t.i.d.
  • the present invention is based on the insight that, when present simultaneously in the body, levamisole and 5-FU interact to provide a chemotherapeutic effect.
  • the effect is not due to a systemic immunomodulatory effect of levamisole, which was the basis for the design of prior art regimens, but is in fact due to a Specific pharmacological interaction of levamisole with one or more of the molecular mechanisms surrounding the action of 5-FU.
  • the invention provides improved methods for potentiating the antineoplastic activity of 5-fluorouracil or its analogues with levamisole, or with analogues thereof.
  • the methods of the invention provide for the consistent contemporaneous administration of levamisole or its analogues with 5-fluorouracil or its analogues, thereby regularly exposing tumor tissue to effective concentrations of levamisole or an analogue at the same time that the tissue is being exposed to 5-FU or an analogue.
  • a further aspect of the present invention is a method for parenteral aclministration of levamisole in conjunction with 5-FU, which enables the consistent attainment of effective blood levels of levamisole in most patients.
  • the methods of the invention may optionally be employed in conjunction with the aclministration of other antitumor agents as well.
  • the methods of the invention are expected to provide superior clinical outcomes to the prior art methods of administering levamisole in conjunction with 5-FU.
  • levamisole and 5-FU are actually administered on the same day only once every fourteen days in the course of therapy, while on three days out of every fourteen only one of the two drugs is given.
  • the serum half-life of levamisole in humans is about four hours (J.M. Reid et al, 1998,
  • the prior art regimen is remarkably far from optimal if, as the present inventor believes, the two drags need to be present simultaneously for the desired clinical therapeutic effect to be obtained. Indeed, the two drugs are present together at significant concentrations in the serum only if oral levamisole is given shortly before the 5-FU infusion. Table 2 illustrates the percentages of treatment days and total days on which one or both drugs are administered.
  • the QUASAR study also provided subjects the option of a "once weekly schedule” if the above "4- weekly schedule” was impracticable.
  • 5-FU is given alone half the treatment days and incidentally given on the same day as levamisole half the treatment days.
  • 5- FU is given alone, whenever it is administered.
  • Levamisole is given on the same day as 5-FU only once in every three days in which levamisole is administered.
  • the "once weekly schedule" and percentage of days with co- administration are shown in Tables 5 and 6.
  • the present invention is based on the re-examination of all of the clinical literature on levamisole, which has revealed that incidental co-administration is the means by which clinical effects were seen.
  • an early study (R. Windle et al, 1987, Br. J. Surg. 74:569-572) introduced a protocol in which patients received intravenous 5-FU immediately following surgery (resection of colon cancer) and on the first two post-operative days, oral levamisole (150 mg/po qd) on the first three post-operative days, and oral 5-FU (without levamisole) once a week for six months thereafter.
  • the route of administration may for example be oral, intravenous, subcutaneous, intramuscular, or intraperitoneal injection or infusion, or injection or infusion directly into the portal vein.
  • the route is intravenous, more preferably it is intravenous infusion.
  • the drug administered by the method of the invention is preferably levamisole, and the drug whose activity is to be potentiated is preferably 5-fluorouracil or capecitabine. Where the drug to be potentiated is 5-fluorouracil, the levamisole or levamisole analogue is most preferably administered contemporaneously.
  • Constants means that the drags are administered within about 90 minutes of each another, preferably within about 30 minutes of each other, and in the case of parenteral administration of levamisole, preferably simultaneously or within 10 minutes of each other. It is preferable that levamisole be administered first.
  • Other drugs may be administered in addition to 5-fluorouracil and levamisole, for example leucovorin and/or ethynyluracil may be administered as an additional chemotherapeutic component.
  • the preferred analogues of levamisole are 4-bromolevamisole and 4-hydroxylevamisole, and prodrugs and pharmaceutically acceptable salts thereof.
  • Preferred salts are hydrochloride and hydrobromide salts.
  • the levamisole or levamisole analogues may be dissolved or suspended in any pharmaceutically acceptable vehicle suitable for parenteral aclministration.
  • Preferred vehicles are sterile water and sterile saline.
  • a conventional dose of levamisole (50 mg) is administered parenterally along with a conventional dose (450 mg/m 2 ) of 5-fluorouracil.
  • additional conventional doses, preferably one or two doses, of levamisole may optionally be administerecLparenterally over the next 24 hours. The procedure is repeated for 5 to 7 days, and weekly thereafter.
  • the first daily dose of levamisole is larger than a conventional oral dose, for example between 75 and 200 mg, preferably between 100 and 150 mg. In these embodiments as well, additional daily doses of levamisole may optionally be administered.
  • the optional daily doses of levamisole are administered orally.
  • This embodiment has the advantage of being more amenable to out-patient treatment, as the attendance of medical personnel are required only once in the course of the day, while the optimum plasma level of levamisole that is provided by parenteral aclministration is obtained at the time the 5-fluorouracil is circulating.
  • leucovorin may be aclministered contemporaneously with levamisole and 5-fluorouracil.
  • orally or parenterally administered capecitabine is substituted for 5-fluorouracil.
  • parenteral levamisole is administered contemporaneously with 5-FU in any one of the "CMF” (cyclophosphamide, methotrexate, and 5-fluorouracil), "CEF” (cyclophosphamide, epirabicin, and 5-fluorouracil), or “CAF” (cyclophosphamide, AdriamycinTM, and 5- fluorouracil) adjuvant chemotherapy regimes for breast cancer, or is administered contemporaneously with 5-FU for the treatment of any cancer for which 5-FU is used alone or in combination with other drags. It is anticipated that contemporaneous administration of levamisole may permit 5-FU to be used to treat cancers that have not previously been treated successfully with 5-FU, for example prostate cancer.
  • CMF cyclophosphamide, methotrexate, and 5-fluorouracil
  • CAF cyclophosphamide, epirabicin, and 5-fluorouracil
  • CAF cyclophosphamide, AdriamycinTM, and 5- fluorour
  • the methods of the invention are not intended to be limited to post-surgical adjuvant therapy, and treatment could be initiated prior to surgical reduction of tumors.
  • parenteral aclministration of levamisole should make it possible to commence adjuvant therapy immediately after colorectal surgery, as there is no need to wait 20 days for healing of the intestinal tract as is typically the case when using oral levamisole.
  • Levamisole hydrochloride (50 mg) is dissolved in pH 7.5 buffered saline (5 ml), and the solution is sterilized by ultrafilrration. The resulting solution is administered intravenously, simultaneously with an intravenous infusion of 450 mg/m 2 of 5-fluorouracil, to a patient who has undergone surgical resection of a colorectal cancer the previous day.
  • Levamisole (50 mg) is administered twice more, at eight-hour intervals, by injection. The process is repeated for five consecutive days, and weekly thereafter for one year.
  • Example 2 The process of Example 1 is carried out, except that the second and third daily doses of levamisole are given orally, and treatment is commenced 20 days after surgery.
  • EXAMPLE 3 Levamisole hydrochloride (100 mg) is dissolved in pH 7.5 buffered saline (5 ml), and the solution is sterilized by ultrafiltration. The resulting solution is administered intravenously, simultaneously with an intravenous infusion of 450 mg/m 2 of 5-fluorouracil, to a patient who has undergone surgical resection of a colorectal cancer the previous day. Levamisole (50 mg) is administered twelve hours later, by injection. The process is repeated for five consecutive days, and weekly thereafter for one year. EXAMPLE 4 The process of Example 3 is carried out, except that the second daily doses of levamisole are given orally, and treatment is commenced 20 days after surgery.
  • EXAMPLE 5 Levamisole hydrochloride (100 mg) is dissolved in pH 7.5 buffered saline (5 ml), and the solution is sterilized by ultrafiltration. The resulting solution is administered intravenously, simultaneously with an intravenous infusion of 450 mg/m 2 of 5-fluorouracil, to a patient who has undergone surgical resection of a colorectal cancer at least 20 days previously. The process is repeated for five consecutive days, and weekly thereafter for one year.
  • Levamisole hydrochloride (100 mg) is dissolved in pH 7.5 buffered saline (5 ml), and the solution is sterilized by ultrafiltration. The resulting solution is administered intravenously, simultaneously with an intravenous infusion of 500 mg/m 2 of 5-fluorouracil, to a patient who has undergone surgical resection of a colorectal cancer at least 20 days previously. The process is repeated once weekly for six consecutive weeks, followed by three weeks without drugs. This nine-week cycle is repeated a total of four times.
  • EXAMPLE 7 Levamisole hydrochloride (100 mg) is dissolved in pH 7.5 buffered saline (5 ml), and the solution is sterilized by ultrafiltration. The resulting solution is administered intravenously, simultaneously with an intravenous infusion of 450 mg/m 2 of 5-fluorouracil, to a patient who has undergone surgical resection of a colorectal cancer. The process is repeated for five consecutive days, followed by three weeks without drags. This four-week cycle is repeated six times.
  • Levamisole hydrochloride (90 mg) is administered orally to a patient who has undergone surgical resection for colorectal cancer 20 days previously. An intravenous infusion of 450 mg/m 2 of 5-fluorouracil is commenced two hours later. The process is repeated for five consecutive days, followed by three weeks without drugs. This four-week cycle is repeated six times.
  • EXAMPLE 9 On day 1 of a 21-day course of chemotherapy, levamisole hydrochloride (90 mg) is administered orally, and within 2 hours intravenous infusions of 500 mg/m 2 of 5-fluorouracil, 50 mg/m 2 of adriamycin, and 500 mg/m 2 of cyclophosphamide are administered, to a patient who has metastatic breast cancer. The process is repeated on day 8. The 21-day course is repeated until a total of 450 mg/m 2 of adriamycin has been administered, and 30 mg/m 2 methotrexate i.m. is substituted for adriamycin tliereafter. Treatment is continued until remission is achieved, and for two additional years beyond that.

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Abstract

L'invention concerne un procédé amélioré de potentialisation de l'activité antinéoplastique du 5-fluorouracile avec du lévamisole, ou avec un analogue de ce composé. Elle concerne spécifiquement des régimes dans lesquels du lévamisole est administré de façon conjuguée à l'administration de 5-fluorouracile, ce qui permet d'augmenter l'exposition d'un tissu tumoral à la présence simultanée des deux médicaments. Elle concerne aussi des procédés d'administration parentérale de lévamisole permettant d'éviter les désavantages associés aux variabilités entre patients de la biodisponibilité par voie orale.
EP01995344A 2000-12-01 2001-12-03 Procede d'administration conjuguee de levamisole et de 5-fluorouracile Withdrawn EP1343434A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US25062900P 2000-12-01 2000-12-01
PCT/US2001/046381 WO2002043618A1 (fr) 2000-12-01 2001-12-03 Procede d'administration conjuguee de levamisole et de 5-fluorouracile
US250629P 2009-10-12

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EP1343434A1 true EP1343434A1 (fr) 2003-09-17
EP1343434A4 EP1343434A4 (fr) 2004-08-18

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AU (2) AU2590202A (fr)
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WO (1) WO2002043618A1 (fr)

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WO1997038725A1 (fr) * 1996-04-12 1997-10-23 The University Of Kentucky Research Foundation Procedes pour retarder le developpement de tumeurs associees a l'antigene carcinoembryogene a l'aide d'un anticorps 3h1 anti-idiotype

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CARPENTER, J.T. JR ET AL.: "Ineffectiveness of levamisole in prolonging remission or survival of women treated with cyclophosphamide, doxorubicin, and 5-fluorouracil for good-risk metastatic breast carcinoma: a Southeastern cancer study group trial" CANCER TREATMENT REPORTS, vol. 70, no. 9, September 1986 (1986-09), pages 1073-1079, XP009032398 *
JONG SOO CHOI ET AL.: "A randomized trial comparing cisplatin plus 5-fluorouracil with or without levamisole in operable gastric cancer" THE KOREAN JOURNAL OF INTERNAL MEDICINE, vol. 12, no. 2, June 1997 (1997-06), pages 155-162, XP009032395 *
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* Cited by examiner, † Cited by third party
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US10272072B2 (en) 2010-09-03 2019-04-30 Forma Tm, Llc Compounds and compositions for the inhibition of NAMPT
US10456382B2 (en) 2010-09-03 2019-10-29 Forma Tm, Llc Compounds and compositions for the inhibition of NAMPT
US10772874B2 (en) 2010-09-03 2020-09-15 Forma Tm, Llc Compounds and compositions for the inhibition of NAMPT
US11547701B2 (en) 2010-09-03 2023-01-10 Valo Health, Inc. Compounds and compositions for the inhibition of NAMPT

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AU2002225902B2 (en) 2006-05-25
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WO2002043618A1 (fr) 2002-06-06
EP1343434A4 (fr) 2004-08-18
CA2430489A1 (fr) 2002-06-06

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