.,.,l
`
`r·
`---~1.
`~~~~lr~ '::·
`
`.... ":.": •• -
`
`~I..
`
`.• ,, ·1
`I
`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`<19> World•·;:::.~":",,,!°"'"'°"'';." •
`
`lllBllHlllllUHllllDllllllHlllDl!mHlllll
`
`(43) International Publication Date
`26 October2006 (26.t0.2006)
`
`PCT
`
`(10) International Publication Number
`WO 2006/111238 Al
`(81) Designated States (unless otherwise indicazed, for every
`kind ofna1ional protection available): AE, AO, AL, AM,
`AT, AU, AZ, BA, BB, BO, BR, B\V. BY. BZ, CA, CH, CN,
`CO, CR, CU, CZ. DE, DK, DM, DZ, EC, EE. EO, BS, Fl,
`OB, GD, GE, OH, GM, HR, HU, ID, Il.., IN, IS, JP, KB,
`KG, KM, KN, KP, KR. KZ. LC, LK, LR, LS, LT, LU, LV,
`LY, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI,
`NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG,
`SK, SL,.SM, SY, Tl, TM, TN, TR, TI, TZ, UA, UG, US,
`UZ, VC, VN, YU, ZA, ZM, 'ZW.
`
`(Sl) International Patent ClasslfkaUon:
`CJZQ 1160 (2006.01)
`CIZQ 1161 (2006.01)
`
`(21) International Application Number:
`PCTIEP2006J002647
`
`(22) International FIUng Date:
`
`12 April 2006 (12.04.2006)
`
`(25) Flllog Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(JO) Priority Data:
`0504060
`
`22 April 2005 (22.04.2005)
`
`FR
`
`(71) Appllcant(jorall designa1ed S1azesezcept US): MERCK
`PATENT GMBH [DFJDE]; Frankfurter Strasse 250,
`64293 Darmstadt (DE).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): CHEVREUIL,
`Olivier [FR/FR); Le Petit Maillard, F-01400 Condeis-
`
`F-69005 Lyon (FR). GUERRIER, Danlel [FR/FR]; 35C,
`Route de Charly, F-69230 Saint Genis Laval (FR). .
`
`(74) Common Representative: MERCK PATENT GMBH;
`Frankfurter Strasse 250, 64293 Dannstadt (DE).
`
`_
`
`-
`
`-
`
`(84) Designated States (unless otherwise indicazed, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE. LS, MW, MZ, NA, SD, SL, SZ, TZ. UG, ZM,
`'ZW), Eurasian (AM, Az, BY, KO, KZ. MD, RU, Tl, TM),
`European (AT, BB, BG, CH, CY, CZ. DB, DK, BE, BS, Fl,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT,
`RO, SB, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA,
`GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`. Published:
`with intenuJlional s1tan:h repon
`-
`
`For two-lertu codes and other abbreviazions, refer to the HGuld(cid:173)
`ance Notes on Codes and Abbreviazions· appearing az the begin(cid:173)
`ning of each regular issue of the PCT G~tte.
`
`(54) Tiue: METHOD R)R SCREENING MTP-INHIBITINO COMPOUNDS
`
`Compound 1
`
`100
`
`90
`
`80
`
`70
`
`= sat (FR). DUPONT, Herve [FR/PR]; 20, rue luiverie,
`==
`--
`-
`- ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
`---
`;;;;;;;;;;;; -
`-
`--
`---
`----
`
`60
`
`50
`
`g
`i
`:E .e 40
`
`~
`
`30
`
`20
`
`10
`
`0
`
`0
`
`60
`
`120
`
`180
`24,0
`300
`llrne after treatment (min)
`
`360
`
`420
`
`480
`
`540
`
`~ (57) Abstract: The present invention relates to a screening method for selecting active materials that inhibit microsomal lriglycerlde
`
`~ transfer protein (MTP) and to a screening kit osing the said method.
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`Method for screening MTP-inhibiting compounds
`
`s
`
`The invention relates to a screening method for selecting specific lnhibi-
`[0001)
`tors of microsomal triglyceride transfer protein· (MTP) which are efficient and have
`a short duration of action.
`MTP (umicrosomal triglyceride transfer protein") is a transfer protein
`[0002)
`located in the reticulum of hepatocytes and enterocytes, which catalyses the
`assembly of biomolecules that transport triglycerides, the apoB ripoproteins.
`
`10
`
`15
`
`The term apoB more particularly denotes apoprotein 848 of the intes-
`[0003)
`tine and apoprotein B100 of the liver, without, however, being limited thereto.
`Mutations in MTP or in the B apoproteins are reflected in man by very
`[0004]
`low levels or even an absence of apoB lipoproteins. The llpoproteins containing
`apoB (chylomicrons, "Very Low Density Lipoproteins" = VLDL) and their metabolic
`residues (chylomlcron remnants, 11Low Density Upoproteins" = LDL) are recog-
`nlsed as being a major risk factor in the development of atherosclerosis, a major
`cause of death in industrialised countries.
`It is observed that, in individuals who are heterozygous for these muta-
`[0005]
`tions, levels reduced on ayerage by. a half are associated with a low cardiovascu(cid:173)
`lar risk (C.J. Glueck, P.S. Gartside, M.J. Mellies, P.M. Steiner, Trans. Assoc. Am.
`20 Physicians, 90, 184 (1977)).
`This suggests that modulation of the secretion of triglyceride-rich lipo(cid:173)
`[0006]
`proteins by means of MTP antagonists and/or of secretion of apoB might be useful
`In the treatment of atherosclerosis and more broadly of pathologies characterised
`by an Increase in apoB lipoproteins.
`Molecules· that inhibit MTP and/or the secretion of apoB might thus be
`[0007]
`useful for the treatment of diabetes-related hypertriglyceridaemia, hypercho(cid:173)
`lesterolaemia and dyslipidaemia, and also for the prevention of and treating obe(cid:173)
`sity.
`
`25
`
`There are already a number of examples in the literature of compounds
`[0008]
`capable of inhibiting MTP, but it Is observed that since the start of the lnvestiga-
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`tions on these inhibitors, none of them has become commercially available. In(cid:173)
`deed, many development projects were stopped after the first clinical trials.
`Specifically, preliminary results of clinical studies support the inhibition
`[0009)
`of MTP as a means of reducing the level of triglycerides and of cholesterol in man.
`However, such a therapy requires a long treatment, extending over several -years.
`The in vivo administration to man of MTP-inhibiting compounds over such long
`periods might give rise to toxic effects, for instance an accumulation of lipids in the
`intestine and the liver, leading, for example, to hepatic steatosis.
`In other words, although an in vitro primary screening test now makes it
`[0010)
`possible to identify potential MTP-inhibiting candidates, the in vivo confirmation
`tests show that many-of these candidates are responsible for toxic effects on the
`liver.
`
`To overcome this problem, it is nowadays proposed, for example, to
`[0011)
`· combine MTP inhibitors with fibrates. However, this type of therapy has the draw-
`backs associated with the administration of two active materials (problems of dos(cid:173)
`age, compatibility, etc.).
`There is consequently still a need for MTP-inhibiting active substances
`[0012)
`that induce few or no toxic side effects, in pa~icular hepatic steatosis.
`Thus, a first object of the invention consists in reducing the levels of
`[0013)
`triglycerides and cholesterol in the blood, without inducing an accumulation of lip(cid:173)
`ids in the liver and in the intestine.
`[0014]
`Another object of the invention consists in providing a screening test for
`selecting compounds capable of reducing hypertriglyceridaemia and cholesterol(cid:173)
`aemia with a lower risk of lipid accumulation in the liver.
`Other objects will become apparent in the description of the invention
`[0015]
`discussed in further detail hereinbelow.
`The present invention Is based on the hypothesis that the liver re-
`[0016)
`secretes the excess accumulated lipids, this excess being inherent to the inhibitory
`activity of the compound, since it is no longer active.
`The inventors have now discovered, surprisingly, that, given that acer-
`[0017)
`tain potency is necessary in order to obtain a sufficient pharmacological effect,
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`only active principles having a short duration of action and liable to give a sufficient
`pharmacological effect ("flash" effect) generate fewer or none of the toxic effects
`observed with inhibitors with a long duration of action.
`
`5
`
`10
`
`15
`
`In addition, since the use in man involves a chronic treatment, it is
`[0018)
`necessary for this recovery phase by the liver to take place between two admini(cid:173)
`strations in order to avoid the accumulation of lipids possibly leading to the devel(cid:173)
`opment of steatosis.
`Consequently, the inventors have, for the first time, used a known
`[0019)
`qualitative test for the selection of MTP-inhibiting candidates, to determine the·
`kinetics of action of the said candidate.
`Thus, the present Invention first proposes-·e.-· screenih!f ·method·-for--·
`[0020)
`selecting active materials that inhibit microsomal triglyceride transfer protein
`(MTP), comprising the steps of:
`a) using a candidate compound in a. test of kinetic monitoring of inhibition of a
`parameter associated with the inhibition of MTP (inhibition of secretion of
`apoB, inhibition of secretion of VLDL and the like);
`b) monitoring of the kinetics of inhibition of the said parameter by the said
`candidate from the start of the test and for a duration of between 3 hours
`and 24 hours, preferably between 5 hours and 12 hours and more pref(cid:173)
`erably between 6 hours· and 10 hours; and
`c) selection of the candidate if it has kinetics of inhibition of the said parame(cid:173)
`ter characterised by:
`I)
`a pereentage of inhibition for the said parameter .of greater
`than or equal to 50% over a maximum duration of less than 4 hours and
`preferably less than 3 hours; and
`a residual inhibitory activity for the said parameter of less than
`ii)
`20% and preferably less than 10%, beyond 10 hours, preferably beyond 8
`hours and more preferably beyond 6 hours, after the start of the test.
`In the screening method of the present invention, the test for kinetic
`[0021]
`30 monitoring of inhibition is referred to as ''Test A" in the rest of the present descrip(cid:173)
`tion.
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`[0022]
`
`Thus, Test A defined above makes it possible to select compounds hav-
`
`ing both sufficient MTP-inhibiting activity, and an absence of residual inhibitory
`
`activity that might result in adverse effects, such as those mentioned above and in
`
`particular hepatic steatosis.
`
`s
`
`[0023]
`
`The term "sufficient MTP-inhibiting activity" means that the percentage
`
`of inhibition observed for the parameter associated with the inhibition of MTP (for
`
`example apoB or VLDL) is at least equal to 50%.
`
`[0024)
`
`The term "residual Inhibitory activity" should be understood as meaning
`
`inhibitory activity o~served for the parameter associated with the inhibition of MTP
`
`10
`
`(for example apoB or VLDL) of less than 20%, preferably less than 10%, and more
`preferably insignificant inhibitory activity-versus placeb-o:--·- ---- - ·-·--- -·----·
`
`In the rest of the present description, the term "reversible" qualifies
`
`[0025)
`compounds with a short duration of action, i.e. those that have the desired ''flash"
`
`· effect, and "irreversible" qualifies compounds with a long duration of action.
`
`is
`
`Test A of the screening method according to the present invention
`
`[0026]
`allows the selection of reversible candidates.
`
`[0027]
`
`This Test A is a kinetic monitoring of inhibition of a parameter associ(cid:173)
`
`ated with the inhibition of MTP, for example a test of Inhibition of the secretion of
`apoprotein B (apoB), advantageously if it is an in vitro test, using hepatic or enteric .
`cells of any type, preferably hepatic cells, such as HepG2 cells, or alternatively a
`
`test of kinetic analysis of inhibition of MTP on the secretion of very low density
`lipoproteins (VLDL). advantageously if it is an in vivo test. The examples that fol(cid:173)
`low show, for illustrative purposes, particular modes of implementation of Test A.
`Test A may be performed in vitro or in vivo. According to one preferred
`[0028)
`variant of the invention, Test A performed in vitro (noted as Avttro in the rest of the
`description) measures the kinetics of secretion of apoB, and Test A performed
`in vivo (noted as Av1vo in the rest of the description) measures the kinetics of secre(cid:173)
`tion of VLDLs.
`In Test Avttro, the candidate compounds are considered as having a
`[0029]
`short duration of action if they show satisfactory reversibility, i.e. if the secretion of
`apoB, 24 hours after removal of the test compound, has returned to a level whose
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`value is greater than or equal to 50% and advantageously greater than or equal to
`70%, relative to a control that has not, by definition, been treated with an inhibitory
`
`compound.
`According to one preferred variant ·of the present invention, Test A is
`[0030)
`.performed In vitro, and the selected candidates are then used in one or more
`
`s
`
`Tests A In vivo, in order to confirm the activity of_ the can_~idate select~d after the
`Test A in vitro.
`Test A is performed in vitro on cells in culture that are preferably hepatic
`[0031)
`cells, advantageously HepG2 cells. Test A·is performed in vivo on a suitable ani-
`10 mal model, for example rats.
`In addition, Test A defined above may be combined with-one or-more-
`[0032)
`other preselection or post-selection tests, allowing faster and/or more specific
`screening for the selection of MTP-inhibiting candidates with a short duration of
`action.
`
`15
`
`20
`
`2s
`
`Thus, in addition to the test of reversibility of action on MTP (the kinetic
`[0033)
`Test A defined above), the screening method according to the invention may be
`followed or preceded by one or more qualitative tests of inhibition of the activity of
`MTP, for instance the test described by Wetterau and Zilversmit (Biochem. Bio(cid:173)
`phys. Acta, (1986), 875-610).
`This test (referred to as Test B hereinbelow) makes it possible to per(cid:173)
`[0034)
`form a qualitative. selection of candidates with regard to their capacity to inhibit or
`otherwise MTP in vitro. By virtue of its nature, this test is advantageously per(cid:173)
`formed before Test A defined above;
`In addition, it may prove to be advantageous to use the candidate prod-
`[0035]
`ucts in a test (referred to as Test C in the rest of the description) of inhibition of
`secretion of apoB, for example in the HepG2 human cell fine, allowing analysis of
`the inhibitory capacity of the candidates on the secretion of apoB.
`Test C is of interest, like Test 8, in particular if it is used before Test A,
`[0036)
`to allow a preliminary screening of "active-inactiveu type. of the test compounds.
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`Test C is also known and commonly used in the field. Reference may
`[0037]
`be made, for example, to Dixon J. and Ginsberg H. (J. Lipid. Res., (1993), 34, 167-
`179) for the implementation of this test.
`The screening method according to the present invention for selecting
`[0038)
`compounds with satisfactory reversibility may, according to another embodiment,
`also comprise one or more tests· for determining whether the plasmatic metabolites
`of the test compounds are active or inactive.
`Specifically, the problem that the present invention proposes to solve
`[0039)
`consists in selecting MTP inhibitors that have satisfactory inhibitory activity but of
`short duration ("flash" effect, reversible inhibitors). Consequently, it is advanta(cid:173)
`geous to ensure that the plasmatic metabolites of the co-mpounds selected or to be
`selected do not themselves have inhibitory activity on the same target, i.e. an IC50
`on MTP activity of greater than 1 µM and preferably greater than 10 µM.
`Thus, Test A may also be preceded or followed, preferably followed, by
`[0040]
`one or more tests of inhibition of MTP and/or of inhibition of the secretion of VLDLs
`and/or of inhibition of the secretion of apoB, which are similar or even identical to
`the Tests B and/or C, respectively, defined above, but performed this time on the
`plasmatic metabolites of the. candidate compounds. These tests on the metabo(cid:173)
`lites will be referred to hereinbelow as Test D (metabolites/MTP inhibition test) and
`Test E (metabolites/apoB inhibition test).
`The term "plasmatic metabolites11 means the products of degradation of
`[0041]
`the candidate compounds by the live body. These metabolites are obtained ac(cid:173)
`cording to any standard method known to those skilled in the art, for example by
`structural determination of the products of degradation of the candidate com-
`pounds after incubation in live cells, preferably in microsomes, followed by resyn(cid:173)
`thesis of the potential metabolites.
`The screening method according to the present invention may be fol(cid:173)
`[0042]
`lowed by one or more tests of confirmation (post-selection) of in vivo activity. Ad(cid:173)
`vantageously, the screening method according to the invention will also include at
`least one in vivo confirmation test chosen from a qualitative test of Inhibition of
`VLDL secretion, similar to the in vitro tesls B and C defined above, and a test of
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`the evaluation of the kinetics of inhibition of VLDL secretion, similar to the in vitro
`test A defined above. These two c.onfirmation tests will be referred to .as test F and
`test Av1vo. respectively.
`[0043]
`Finally, the candidates that have responded positively to the tests se-
`lected from those defined above may be subjected to a final test (Test H), in vivo,
`for determination of the desired pharmacological effect (reduction of triglycerides
`in the blood). This Test H may be of any known type, for example of the type pre(cid:173)
`sented in the examples that follow.
`All of the tests described above, which complement/confirm test A in the
`[0044]
`screening method according to the invention are collated in the table below in
`chronological order;-which constitutes-a-preferred variant_of.the-screeriihg mettiOd
`according to the invention, with mention of the test target, i.e. animal model (in
`particular ra~s) for the In vivo tests, and HepG cells, MTP proteins or any other
`type of liver cell for the in vitro tests:
`
`s
`
`10
`
`15
`
`I Substrate
`
`I Target
`
`Candidate
`Candidate
`l Candidate
`
`I HepG2 cells
`
`l in vitro/ in vivo
`I Test
`Preselection
`B
`in vitro
`in vitro
`C
`Selection
`I Awrro I in vitro
`Tests on the metabolites
`Metabolites MTP proteins
`in vitro
`D
`E
`Metabolites HepG2 cells
`in vitro
`Post-selection - Confirmation
`Candidate
`In vivo
`F
`Candidate
`in vivo
`Av1vo
`
`H
`
`in vivo
`
`Candidate
`
`- animal -
`
`-.animal -
`- animal -
`
`I Description
`
`MTP inhibition/ ualitative
`a B inhibition/ ualitative
`I apoB inhibition/kinetics
`
`MTP inhibition/qualitative
`aooB inhibition/qualitative
`
`VLDL inhibition/qualitative
`VLDL inhibition/kinetics
`Desired phannacological
`effect (reduction of triglyc-
`erides in the blood)
`
`It is clearly understood that the kinetic Test A can be used as sole test,
`[0045]
`in vivo or in vitro, for the determination of MTP-inhibiting compounds with a short
`duration of action. It will be noted, however, that if Test Av1tm is used alone in the
`said method, it will advantageously be followed by a Test Av1vo of kinetic analysis of
`the inhibitory power of the candidate compound.
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`According to one preferred embodiment, the invention relates to a
`[0046)
`method for screening MTP-inhibiting compounds, comprising the selection of can(cid:173)
`didates by means of a Test Av1tro as defined above, followed by the selection of the
`candidates that have responded positively to the Test Av1tro by means of a Test
`
`Aviva·
`According to another-embodiment,-the-invention-relates-to-a-method-for(cid:173)
`[0047)
`screening MTP-inhlbitlng compounds, comprising a preselection of candidates
`chosen from those that have responded positively to Test Band/or to Test C de(cid:173)
`fined above, selection from the candidates derived from the preselection by means
`of a Test Av1tro as defined above, and then selection of the candidates that have
`responded positively to Test Av1tm by means of a Test Av1vo.
`[0048]
`According to yet another embodiment, the present invention relates to a
`screening method comprising the steps of:
`using candidate compounds in a Test Band/or a Test C, followed by
`a)
`preselection of the candidates responding positively to the said Test B and/or to
`the said Test C;
`b)
`using the candidate compounds derived from step a) in a Test A, and
`advantageously a Test Av1tro. and selection of the candidates responding positively
`to the said Test A;
`c)
`optional additional ·selection of the candidate compounds selected
`from step b), via analysis of the metabolites of the said candidates by means of a
`Test D and/or a Test E;
`d)
`using the candidate compounds selected during steps a), b) and c) in
`at least one in vivo confirmation test F and/or Av1vo, followed by selection of the
`candidates responding positively to Test F and/or to Test Av1vo; and
`e)
`confirmation of the candidates selected during the preceding step, by
`selection using an in vivo Test H of control of the reduction of triglycerides in the
`blood.
`The implementation of the various tests described above is preferably
`[0049)
`performed in the order Band/or C -Av11ro - D and/or E - F and/or Av1vo - H, without
`this order constituting any limitation of the present invention.
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`The present invention also relates to the use of the screening method
`[0050)
`according to the invention comprising at least one Test Av1tro, a Test Av1vo or a com(cid:173)
`
`bination of the two, as defined above, to determine the kinetics of a parameter as(cid:173)
`sociated with the inhibition of MTP .bY a candidate compound. The conditions for
`performing these tests are those described in the screening method.
`
`5
`
`Preferably, this ~est is used to determine _whether tile_ can~ida~_ COJTI- __
`[0051)
`pound has a short duration of action ("flash" effect) within the meaning of the pre(cid:173)
`sent invention, or, on the contrary, a long duration of action.
`The present invention also relates to a screening kit for selecting active
`[0052)
`10 materials that inhibit microsomal triglyceride transfer protein (MTP) using the
`--
`screening method as defined above-:- --
`The screening kit is consequently defined as compnsmg all of the
`[0053]
`means for performing at least one Test A, Test Av1tro and/or Test Avtvo. defined
`above, and optionally one, several or all of the tests B to H defined above, in any
`order.
`
`15
`
`The compounds selected via the screening method according to the
`[0054)
`invention, or selected by using the kit defined above, have an entirely advanta(cid:173)
`geous possible application in the treatment of hypertriglyceridaemia, hypercho(cid:173)
`lesterolaemia and dyslipidaemia associated with metabolic syndrome and diabe.:.
`tes, and pancreatitis, but also for the prevention of and treating obesity.
`Thus, the MTP inhibitors with a short duration of action selected via the
`[0055]
`screening method according to the present invention induce a significant reduction
`in hypertriglyceridaemia in obese Zucker rats (fatty fa/fa), an animal model of
`hypertriglyceridaemia, without aggravating the lipid content of the liver (steatosis),
`as is observed, on the contrary, with an MTP inhibitor with a long duration of
`action.
`
`According to another aspect, the present invention consequently also
`[0056)
`relates to the compounds selected via the screening method according to the in(cid:173)
`vention or by means of the kit according to the present invention. They can be
`used for the preparation of a medicament for _the treatment of hypertriglyceridae-
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`PCT/EP2006/002647
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`-10-
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`mia, hypercholesterolaemia and dyslipidaemia associated with metabolic syn(cid:173)
`
`drome and diabetes, but also for the prevention of and treating obesity.
`For purely illustrative purposes, compounds 1 and 2 described in patent
`
`[0057]
`
`application FR 2 816 940 {and WO 02/42291) are MTP-inhibiting compounds with
`
`s
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`a short duration of action.
`
`F-- ---F-----· - - ·· --------------
`F
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`1
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`2
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`The present invention also relates to a process for the preparation or
`[0058)
`10 manufacture of a pharmaceutical composition, comprising a screening method ·
`according to the invention, which leads to the selection of a compound of pharma(cid:173)
`ceutical interest, and the mixing of this compound with a pharmaceutically accept(cid:173)
`able vehicle or excipient.
`
`The invention relates especially to such a process for the preparation or
`[0059)
`1s manufacture of a medicament for the treatment of lipid deregulation, such as
`hypertriglyceridaemia, hypercholesterolaemia and dyslipidaemia associated with
`metabolic syndrome and diabetes, but also for the prevention of and treating obe(cid:173)
`sity.
`
`20
`
`The preparation or manufacturing process preferably comprises the im-
`
`[0060]
`plementation of the screening method according to the invention, comprising at
`least one Test Avttro and/or at least one Test Avtvo defined above, to which it is pos- ·
`sible to add one or more of the additional tests defined above, i.e. one, several or
`all of the Tests B to H defined above, in any order.
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`-11-
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`The present invention also relates to the pharmaceutical compositions
`[0061)
`or medicaments that may be obtained by performing the process that has just
`
`been described.
`invention relates more generally to pharmaceutical
`The present
`[0062)
`compositions comprising a pharmaceutically effective amount· of a compound se(cid:173)
`lected via the screening method of the Invention or via the screening kit according
`to the invention, in combination with one or more pharmaceutically acceptable
`vehicles or excipients.
`These compositions may be administered orally in the form of immedi-
`[0063)
`ate-release or controlled-release tablets, gels or granules, or in liquid form, e.g. a
`syrup, intravenously in theform-of an injectable solution, transdermally in the form
`of an adhesive transdermal device, or locally in the form of a solution, cream or
`gel.
`
`A solid composition for oral administration is prepared by adding to the
`[0064)
`compound selected via the screening method of the invention or via the screening
`kit according to the invention a filler and, where appropriate, a binder, a disinte(cid:173)
`grating agent, a lubricant, a colorant or a flavour enhancer, and by forming the
`mixture into a tablet, a coated tablet, a granule, a powder or a capsule.
`Examples of fillers include lactose, com starch, sucrose, glucose, sorbi-
`[0065)
`tol, crystalline cellulose and silicon dioxide, and examples of binders include
`poly(vinyl alcohol), poly(vinyl ether), ethylcellulose, methylcellulose, acacia, gum
`tragacanth, gelatifle, Shellac, hydroxypropylcellulose, hydroxypropylmethylcellu(cid:173)
`lose, calcium citrate, dextrin and pectin.·
`Examples of lubricants include magnesium stearate, talc, polyethylene
`[0066)
`glycol, silica and hardened plant oils. The colorant may be any colorant permitted
`for use in medicaments.
`Examples of flavour enhancers include cocoa powder, mint in herb
`[0067]
`form, aromatic powder, mint in oil form, bomeol and cinnamon powder. It should
`be understood that the tablet or granule may be suitably coated with sugar, gelatin
`or the like.·
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`-12-
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`An injectable fonn comprising the compound,. selected via the screening
`[0068]
`method of the invention or via the screening kit according to the invention as active
`principle is prepared, where appropriate, by mixing the said compound with a pH
`regulator, a buffer agent, a suspension agent, a solubiliser, a stabiliser, a tonicity
`agent and/or a preserving ·agent, and by converting the mixture into a fonn for
`intravenous, subcutaneous or intramuscular injection, according to a conventional
`process. Where appropriate, the injectable fonn obtained may be lyophilised via a
`conventional process. ·
`Examples of suspension agents include methylcellulose, polysorbate
`[0069)
`80, hydroxyethylcellulose, acacia, powdered gum tragacanth, sodium carboxy(cid:173)
`methylcellulose and polyethoxylated sorbitan monolaurate.
`Examples of solubilisers include castor oil solidified with polyoxyethyl(cid:173)
`[0070]
`ene, polysorbate 80, nicotinamide, polyethoxylated sorbitan monolaurate and the
`ethyl ester of castor oil fatty acid.
`In addition, the ·stabiliser includes sodium sulfite, sodium metasulfrte
`[0071]
`and ether, while the preserving agent includes methyl para-hydroxybenzoate, ethyl
`para-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.
`The effective administration doses and posologies of the compounds
`[0072]
`selected via the screening method of the invention or via the screening kit accord-
`ing to the invention, intended for the prevention or treatment of a disease, disorder
`or condition caused by or associated with modulation of MTP activity, depends on
`a large number of factors, for example on the nature of the inhibitor, the size of the
`patient, the desired aim of the treatment, the nature of the pathology to be treated,
`the specific phannaceutical composition used and the observations and the con-
`
`clusions of the treating physician.
`For example, in the case of an oral administration, for example a tablet
`[0073]
`or a gel capsule, a possible suitable dosage of the compounds selected via the
`screening method of the invention or via the screening kit according to the inven(cid:173)
`tion is between about 0.1. mg/kg and about 100 mg/kg of body weight per day,
`preferably between about 0.5 mg/kg and about 50 mg/kg of body weight per day,
`more preferably between about 1 mg/kg and about 10 mg/kg of body weight per
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`-13-
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`s
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`10
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`is
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`day and more preferably between about 2 mg/kg and about 5 mg/kg of body
`weight per day of active material.
`[007 4)
`If representative of body weights of 10 kg and 100 kg are considered in
`order to illustrate the oral daily dosage range that can be used and as described
`above, suitable dosages of the compounds selected via the screening method of
`the invention or via the screening kit according to the invention will be between
`about 1-10 mg and 1000-10 000 mg per day, preferably between about 5-50 mg
`and 500-5000 mg per day, more preferably between about 10.0-100.0 mg and
`100.0-1000.0 mg per day and even more preferably between about 20.0-200.0 mg
`and about 50.0-500.0 mg per day of active material comprising a preferred com(cid:173)
`pound.
`These dosage ranges represent total amounts of active material per
`[0075)
`day for a given patient. The number of administrations per day at which a dose is
`administered may vary within wide proportions depending on pharmacokinetic and
`pharmacological factors, such as the half-life of the active material, which reflects
`its rate of catabolism and clearance, and also the minimum and optimum levels of
`the said active material, in blood plasma or in other bodily fluids, which are
`reached in the patient and which are required for therapeutic efficacy.
`[0076)
`Many other factors should also be taken into consideration when deter-
`20 mining the number of dally administrations and the amount of active material that
`should be administered in a single dosage intake. Among these other factors, and
`not the least of which, is the individual response of the patient to be treated.
`[0077]
`The pharmaceutical compositions as have just been defined are
`preferably intended for the treatment ·of lipid deregulation, such as hypertriglyceri-
`daemia, hypercholesterolaemia and dyslipidaemia associated with metabolic syn(cid:173)
`drome and diabetes, and pancreatitis, but also for the prevention of and treating
`obesity.
`The present invention also relates to a method for the treatment of lipid
`[0078]
`deregulation, such as hypertriglyceridaemia, hypercholesterolaemia and dyslipi-
`daemia associated w