BlO
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`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll 111111111111111111111111111111111
`
`(10) International Publication Number
`WO 2008/090198 Al
`l\iarie [BE/BE]; Route de Bergister, Grandmenil 1,
`B-6960 Manhay (BE). ROEVENS, Peter Walter Maria
`[BE/BE]; Turnhoutseweg 30, B-2340 Beerse (BE).
`
`(81) Designated States (unless othe1Wise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA,
`CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE,
`EG, ES, Fl, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID,
`IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC,
`LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN,
`MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH,
`PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV,
`SY, Tl, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN,
`ZA,ZM,ZW.
`
`(84) Designated States (unless othe1Wise indicated, 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, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MT, NL,
`NO, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG,
`CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`with international search report
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`( 43) International Publication Date
`31July2008 (31.07.2008)
`
`PCT
`
`(51) International Patent Classification:
`A61K 31121 (2006.01)
`A61K 311445 (2006.01)
`A61K 311216 (2006.01)
`A61K 3114468 (2006.01)
`A61K 3114045 (2006.01)
`A61K 311496 (2006.01)
`A61K 3114155 (2006.01)
`A61P 9110 (2006.01)
`
`(21) International Application Number:
`PCT/EP2008/0508 l 4
`
`(22) International Filing Date: 24 January 2008 (24.01.2008)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`07101162.1
`
`25 January 2007 (25.01.2007) EP
`
`(71) Applicant
`(for all designated States except US):
`JANSSEN PHARMACEUTICA NV [BE/BE]; Turn(cid:173)
`houtseweg 30, B-2340 Beerse (BE).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): KING, Peter John
`[GB/BE]; c/o Janssen Pharmaceutica NV, Turnhout(cid:173)
`seweg 30, B-2340 Beerse (BE). HRUPKA, Brian Joel
`[US/BE]; c/o Janssen Pharmaceutica NV, Turnhoutseweg
`30, B-2340 Beerse (BE). BORGHYS, Herman Karel
`[BE/BE]; c/o Janssen Pharmaceutica NV, Turnhoutseweg
`30, B-2340 Beerse (BE). BERWAER, Monique Jenny
`
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`M
`(54) Title: USE OF MTP INHIBITORS FOR INCREASING LEVELS OF SATIETY HORMONES
`~ (57) Abstract: The present invention relates to the use of inhibitors of microsomal triglyceride transfer protein (MTP) for increasing
`
`~ plasma levels of the satiety hormones such as GLP-1, PYY and CCK.
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`USE OF MTP INHIBITORS FOR INCREASING LEVELS OF SATIETY HORMONES
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`[0001] The present invention relates to the use of inhibitors of microsomal
`triglyceride transfer protein (MTP) for increasing plasma levels of the satiety hormones
`such as GLP-1, PYY and CCK.
`
`[0002] Microsomal triglyceride transfer protein (hereinafter referred to as MTP) is
`known to catalyze the transport of triglyceride, cholesteryl ester and phospholipids
`such as phosphatidylcholine. This indicates that MTP is required for the synthesis of
`Apo B-containing lipoproteins such as chylomicrons and VLDL, the precursor to LDL.
`It therefore follows that an MTP inhibitor would inhibit the synthesis of VLDL and
`chylomicrons, thereby lowering levels of VLDL, LDL, cholesterol and triglyceride in
`humans. Compounds capable of inhibiting MTP are believed to be useful in the
`treatment of disorders such as obesity, hyperlipidemia, hypercholesterolemia,
`hypertriglyceridemia, class II diabetes, atherosclerosis and for the reduction of
`postprandial serum triglyceride plasma levels.
`
`[0003] Satiety hormones are hormones released from the gastrointestinal tract in
`response to changes in the nutritional state. These hormones influence central
`mechanisms involved in the regulation of energy balance, through a range of
`bloodborne and neural pathways.
`
`[0004] Glucagon-like peptide 1 (GLP-1) is an intestinal hormone which generally
`stimulates insulin secretion during hyperglycemia, suppresses glucagon secretion,
`stimulates (pro) insulin biosynthesis and decelerates gastric emptying and acid
`secretion. GLP-1 is secreted from L cells in the small and large bowel following the
`ingestion of fat and proteins. GLP-1 has been implicated as a possible therapeutic
`agent for the management of type 2 non-insulin-dependent diabetes mellitus as well
`as related metabolic disorders, such as obesity.
`
`[0005] Pancreatic polypeptide ("PP") was discovered as a contaminant of insulin
`extracts and was named by its organ of origin rather than functional importance.
`A related peptide was subsequently discovered in extracts of intestine and named
`Peptide YY ("PYY") because of the N- and C-terminated tyrosines (Tatemoto, Proc.
`Natl. Acad. Sci. USA, 79: 2514 -2518 (1982)). PYY is secreted from the endocrine L
`cells of the small and large bowel, with high concentration at the terminal ileum, colon
`and maximum concentration in the rectum. Plasma PYY levels are suppressed in the
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`fasted state and increase within 30 minutes of nutrients reaching the gut. PYY release
`is stimulated by nutrient intake in proportion to energy content. It is particularly
`stimulated by fat intake, compared to carbohydrate and protein meals with a similar
`calorie content. Recent studies suggest that PYY can induce appetite reduction.
`
`[0006] Cholecystokinin is structurally related to gastrin and exists in several
`molecular forms with differing numbers of amino acids - examples include CCK-8,
`CCK-33, CCk-39 and CCK-54. CCK is an endogenous gut hormone found mainly
`within the duodenum and jejunum and is released following the consumption of food.
`Release of CCK has been shown to be a satiety signal in humans. When food is
`consumed, CCK releasing protein (CCKRP) is released in the small intestine. CCKRP
`stimulates CCK release from the intestinal cells. It has been shown that CCK release
`results in appetite reduction so that the person will stop eating.
`
`[0007] The ability of CCK to reduce appetite appears to make it a useful agent in the
`treatment of obesity. An increase in the level of the satiety hormone CCK would result
`in less food consumed and reduction of hunger cravings between meals. These
`effects would enable an overweight individual to better comply with a diet that has a
`reduced caloric intake.
`
`[0008] An increase in the level of the satiety hormone CCK extends the feeling of
`satiety, resulting in a decrease of food intake which over time results in a decrease in
`body weight while providing better regulation of glucose and insulin levels following
`consumption of a meal. The release of CCK also causes a delay in stomach emptying
`which blunts the post-prandial rise in glucose and insulin. Most persons with Type II
`diabetes are obese and have an inability to respond normally to insulin. An increase in
`CCK levels may permit Type II diabetics to be satiated with a lower caloric intake and
`may offer a better degree of glycemic control.
`
`[0009] Bulimia is an eating disorder characterised by an inability to become satiated
`by food. As a result bulimics tend to binge on food and regurgitate it to prevent weight
`gain. Studies have shown that bulimics have a defect in their normal satiety
`mechanism. Hence an increase of the satiety hormones would permit bulimics to feel
`satiated.
`
`[0010] Unexpectedly it has now been observed that when inhibitors of microsomal
`triglyceride transfer protein (MTP) are administered to a mammalian subject, the
`plasma levels of the satiety hormones such as GLP-1, PYY and CCK are increased.
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`[0011] The present invention provides the use of a MTP inhibiting compound for the
`manufacture of a medicament for increasing the levels of satiety hormones, such as
`the GLP-1, PYY and CCK hormones. Also provided is the use of a pharmaceutical
`composition comprising a MTP inhibiting compound for the manufacture of a
`medicament for increasing the levels of satiety hormones, such as the GLP-1, PYY
`and CCK hormones.
`
`[0012] Further, the present invention provides a method for increasing the levels of
`satiety hormones, in particular GLP-1, PYY and CCK, in a mammalian subject, which
`method comprises administering to a mammal a therapeutically effective amount of an
`MTP inhibiting compound or a pharmaceutical composition comprising a MTP
`inhibiting compound.
`
`[0013] The use of MTP inhibiting compound for increasing the levels of satiety
`hormones, in particular the GLP-1, PYY and CCK hormones, also has a lowering
`effect on the level of glucose in blood plasma and increases insulin sensitivity. Insulin
`resistance is the condition in which normal amounts of insulin are inadequate to
`produce a normal insulin response from fat, muscle and liver cells. Insulin resistance
`in fat cells results in hydrolysis of stored triglycerides, which elevates free fatty acids in
`the blood plasma. Insulin resistance in muscle reduces glucose uptake whereas
`insulin resistance in liver reduces glucose storage, with both effects serving to elevate
`blood glucose. High plasma levels of insulin and glucose due to insulin resistance
`often leads to the metabolic syndrome and type 2 diabetes.
`
`[0014] Studies in dogs with an induced dilated cardiomyopathy have shown that a
`48 hour of GLP-1 infusion improved the left ventricular function, and reduced systemic
`vascular resistance compared with saline-treated control animals (Nikolaidis LA et al.,
`Circulation 2004; 110:955-961 ). Accordingly the present invention also relates to the
`use of MTP inhibiting compounds for increasing the levels of the satiety hormone
`GLP-1 for the treatment of cardiomyopathy.
`
`[0015] Studies in rats with pyridoxine induced peripheral sensory neuropathy
`suggest neuroprotection mediated by agonism at the GLP-1 receptor (Perry T. et al,
`Experimental Neurology 2007:203, 293- 301). Accordingly the present invention also
`relates to the use of MTP inhibiting compounds for increasing the levels of the satiety
`hormone GLP-1 for the treatment of peripheral neuropathies.
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`[0016] MTP inhibiting compounds have been disclosed in, e.g., Janssen
`Pharmaceutica : W0-96/13499, W0-02/20501, W0-02/42271, W0-02/081460,
`W0-2005/058824, and W0-2005/085226; Bristol-Myers-Squibb : EP-0,584,446,
`EP-0,643,057, W0-96/26205, W0-97/26240, W0-91/43255, W0-97/43257,
`5 W0-98/27979, and W0-99/21564; GSK: W0-98/16526, W0-98/47877,
`W0-98/56790, W0-00/32582, W0-01/92241, W0-01/96327, and W0-03/048121;
`Japan Tobacco : W0-99/31085, W0-03/072532, and W0-2006/008962; Meji Seika
`Kaisho: W0-98/54135; Novartis: W0-01/77077 and W0-2000/005201; Pfizer:
`W0-96/40640, and W0-98/23593.
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`[0017] Particular MTP inhibiting compounds are, e.g., dirlotapide or (S)-N-{2-
`
`[benzyl(methyl)amino]-2-oxo-1-phenylethyl}-1-methyl-5-[4'-(trifluoromethyl)[1, 1 '(cid:173)
`
`biphenyl]-2-carboxamido]-1 H-indole-2-carboxamide; BMS201038 or N-(2,2,2-
`
`trifluoroethyl)-9-[4-[4-[[( 4' -trifluoromethyl)-1 , 1 '-biphenyl-2-yl]carbonyl]amino )-1-
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`piperidinyl]butyl]-9H-fluorene-9-carboxamide (EP-0,643,057); mitratapide or (-)-[2S(cid:173)
`
`[2a,4a(S*)]]-4-[4-[4-[4-[[2-(4-chlorophenyl)-2-[[(4-methyl-4H-1,2,4-triazol-3-
`
`yl)thio]methyl]-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-
`
`( 1-methylpropyl)-3H-1,2,4-triazol-3-one (W0-96/13499); (+)-phenyl-( 4-{4-[(4 '(cid:173)
`
`trifluoromethyl-biphenyl-2-carbonyl)-amino ]-phenyl}-piperidin-1-yl)-acetic acid methyl
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`ester (W0-02/20501 ); JTT-130 or diethyl ester[[[[3-[(dimethylamino)carbonyl]-4-[[[4'(cid:173)
`
`(trifluoromethyl)[1, 1 '-biphenyl]-2-yl]carbonyl]amino]phenyl]acetyl]oxy]methyl]phenyl
`
`propanedioic acid (W0-2006/008962); Slx 4090 from Surface Logix; NA-2003 from
`
`Meiji Seika Kaisha; [(2R)-2,3-dihydro-5-[[[6-methyl-4'-(trifluoromethyl)[1, 1 '-biphenyl]-2-
`
`yl]carbonyl]amino]-1 H-inden-2-yl]-carbamic acid methyl ester (W0-2000/005201 );
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`T-0126 or N-[2-[2-( 1 H-Pyrazol-1-yl)acetyl]-2,3-dihydro-1 H-isoindol-5-yl]-2-[5-
`
`(trifluoromethyl)pyridin-2-yl]benzamide from Tanabe Seiyaku (W0-2002/014276).
`
`[0018] As used herein, "mammal" or "mammalian subject" refers to human and non(cid:173)
`human patients.
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`[0019] As used herein, a "therapeutically effective amount" of a MTP inhibiting
`
`compound, is the quantity of a compound which, when administered to a mammalian
`
`subject, results in a sufficiently high level of that MTP inhibiting compound in the
`
`mammalian to cause a discernible increase of the blood plasma levels of the satiety
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`[0020] The pharmaceutical compositions comprising a MTP inhibiting compound can
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`be administered to a subject either orally, parenterally (for example intravenously,
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`intramuscularly or subcutaneously), percutaneously, or rectally.
`
`[0021] Solid dosage forms for oral administration include capsules, dragees, tablets,
`
`powders and granules. These solid dosage forms are preferably formulated in dosage
`
`unit form for ease of administration and uniformity of dosage. "Dosage unit form" as
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`used herein refers to physically discrete units suitable as unitary dosages, each unit
`
`containing a predetermined amount of active ingredient calculated to produce the
`
`desired therapeutic effect in association with the required pharmaceutical carrier.
`
`Examples of such dosage unit forms are tablets (including scored or coated tablets),
`
`capsules, pills, powder packets, wafers, injectable solutions or suspensions,
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`teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
`
`[0022] Liquid dosage forms for oral administration include pharmaceutically
`
`acceptable emulsions, solutions, suspensions, suspo-emulsions, syrups and elixirs.
`
`Pharmaceutical compositions for parenteral injection may comprise physiologically
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`acceptable sterile aqueous or nonaqueous solutions, dispersions, suspension, or
`
`emulsions, or may comprise sterile powders for reconstitution into sterile injectable
`
`solutions or dispersions.
`
`Description of the drawings
`[0023] Figure 1 is a graph displaying plasma CCK (pMol/I) expressed as the median
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`value per group just before the meal and 12 and 24 hours after the meal.
`
`[0024] Figure 2 is a graph displaying the postprandial plasma PYY (pMol/I) levels
`after 0.02% (w/w) administration of the MTP inhibitor "compound A" mixed in diet
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`containing 17 .5% (w/w) (35 kcal%) fat.
`
`[0025] Figure 3 is a graph displaying the postprandial plasma GLP-1 (pg/I) levels
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`after 0.02% (w/w) administration of the MTP inhibitor "compound A" mixed in diet
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`containing 17.5% (w/w) (35 kcal%) fat.
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`Experimental part
`Experiment 1 : Plasma CCK levels - single dose study in dog
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`[0026] The effect of the MTP inhibitor (+)-phenyl-(4-{4-[(4'-trifluoromethyl-biphenyl-2-
`
`carbonyl)-amino]-phenyl}-piperidin-1-yl)-acetic acid methyl ester (W0-02/20501)
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`(hereinafter referred to as "compound A") on CCK plasma levels was studied in
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`3 groups of 8 dogs each (4 male and 4 female dogs per group). Two groups were
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`treated orally with two different doses of compound A and one group was treated orally
`
`with the vehicle and served as a placebo group. The vehicle solution contained the
`
`same ingredients as the test formulations with omission of the test substance
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`compound A.
`
`[0027] The treatment groups were:
`- group (1) treated orally with vehicle
`- group (2) treated orally with 0.15 mg compound A per kg body weight
`- group (3) treated orally with 0.63 mg compound A per kg body weight
`
`[0028] Dosing with either vehicle (group 1) or compound A (groups 2 and 3) was
`done together with a liquid meal at 7.00 hour for the first two males and females of
`each group and at 18.30 h for the last two males and females of each group. CCK
`plasma levels were determined before dosing, 0 hour, and at 12 and 24 hours post
`feeding.
`
`[0029] As seen in Figure 1, plasma CCK (pMol/I) expressed as the median value per
`group just before the meal and 12 and 24 hours after the meal showed a dose related
`increase of plasma CCK levels after administration of the MTP inhibiting compound A.
`
`Experiment 2 : Plasma PYY levels - study in rats
`
`[0030] Male Sprauge-Dawley rats (lffa-Credo) are housed in individually ventilated
`cages under controlled temperature (20-24°C), humidity (45-65%) and light (12-12h
`light/dark cycle; Lights on - 5 AM - 5PM). Rats were adapted to a semipurified casein,
`cornstarch and sucrose based diet (AIN-93) containing 17.5% w/w corn oil as the fat
`source for 10 days. The 17 .5% diet is calculated to contain 35% of energy as fat.
`
`[0031] At dark onset on day 11, half the rats were switched to the same diet
`containing 0.02% w/w of "compound A", while the remaining rats received the
`control/adaptation diet. At 0, 1, 2, 4, 6, 12, 14, 16, 20 and 24 hr after diet presentation,
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`a group of 6 rats/treatment were killed by decapitation and 4 ml of trunk blood was
`collected in pre-cooled (4°C) K3E plasma tubes containing protease inhibitor cocktail.
`Blood was centrifuged (1500 x g for 15 minutes at 4°C) within 10-15 minutes of sample
`collection taking blood sample and stored at -70°C until assayed.
`
`Experiment 3 : Plasma GLP-1 levels - study in rats
`
`[0032] Male Sprauge-Dawley rats (lffa-Credo) are housed in individually ventilated
`cages under controlled temperature (20-24°C), humidity (45-65%) and light (12-12h
`light/dark cycle; Lights on - 5 AM - 5PM). Rats were adapted to a semipurified casein,
`cornstarch and sucrose based diet (AIN-93) containing 17.5% w/w corn oil as the fat
`source for 10 days. The 17 .5% diet is calculated to contain 35% of energy as fat.
`
`[0033] At dark onset on day 11, half the rats were switched to the same diet
`containing 0.02% w/w of "compound A", while the remaining rats received the
`control/adaptation diet. At 0, 1, 2, 4, 6, 12, 14, 16, 20 and 24 hr after diet presentation,
`a group of 6 rats/treatment were killed by decapitation and 4 ml of trunk blood was
`collected in pre-cooled (4°C) K3E plasma tubes containing protease inhibitor cocktail.
`Blood was centrifuged (1500 x g for 15 minutes at 4°C) within 10-15 minutes of sample
`collection taking blood sample and stored at -70°C until assayed.
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`Claims
`1. Use of a MTP inhibiting compound for the manufacture of a medicament for the
`treatment of a disease mediated by increasing the levels of satiety hormones.
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`2. Use according to claim 1 wherein the satiety hormones are GLP-1, PYY and CCK.
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`3. Use according to claim 2 wherein the satiety hormone is GLP-1.
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`4. Use according to claim 2 wherein the satiety hormone is PYY.
`
`5. Use according to claim 2 wherein the satiety hormone is CCK.
`
`6. Use of a MTP inhibiting compound for the manufacture of a medicament for
`increasing the levels of the satiety hormones GLP-1, PYY and CCK and
`concomitant lowering of glucose levels.
`
`7. Use of a MTP inhibiting compound for the manufacture of a medicament for
`increasing the levels of the satiety hormones GLP-1, PYY and CCK and
`concomitant lowering of insulin sensitivity.
`
`8. The use as claimed in claim 2 wherein the disease is cardiomyopathy.
`
`9. The use as claimed in claim 2 wherein the disease is peripheral neuropathies.
`
`10. The use according to any of claims 1 to 9 wherein the MTP inhibiting compound is
`selected from dirlotapide, N-(2,2,2-trifluoroethyl)-9-[4-[4-[[(4'-trifluoromethyl)-1, 1 '(cid:173)
`biphenyl-2-yl]carbonyl]amino )-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide; (-)(cid:173)
`[2S-[2a,4a(S*)]]-4-[4-[4-[4-[[2-( 4-chlorophenyl)-2-[[( 4-methyl-4H-1,2,4-triazol-3-
`yl)thio]methyl]-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-
`dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one; (+)-phenyl-( 4-{4-[(4'(cid:173)
`trifluoromethyl-biphenyl-2-carbonyl )-amino ]-phenyl}-piperid in-1-yl)-acetic acid
`methyl ester; diethyl ester[[[[3-[(dimethylamino )carbonyl]-4-[[[4'-(trifluoromethyl)(cid:173)
`[1, 1 '-biphenyl]-2-yl]carbonyl]amino]phenyl]acetyl]oxy]methyl]phenyl propanedioic
`acid; [(2R)-2,3-dihydro-5-[[[6-methyl-4'-(trifluoromethyl)[1, 1 '-biphenyl]-2-yl]-
`carbonyl]amino]-1 H-inden-2-yl]-carbamic acid methyl ester (W0-2000/005201 ); or
`N-[2-[2-( 1 H-pyrazol-1-yl)acetyl]-2,3-dihydro-1 H-isoindol-5-yl]-2-[5-
`(trifl uoromethyl )pyrid i n-2-yl]benzam ide.
`
`11. The use according to claim 10 wherein the MTP inhibiting compound is (-)-[28-
`[2a,4a(S*)]]-4-[ 4-[ 4-[ 4-[[2-( 4-chlorophenyl)-2-[[ ( 4-methyl-4H-1 ,2,4-triazol-3-
`
`40
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`- 9 -
`
`yl)th io ]methyl]-1 ,3-dioxolan-4-yl]meth oxy ]phenyl]-1-piperazi nyl] phenyl]-2,4-
`d ihyd ro-2-( 1-methylpropyl)-3H-1,2,4-tri azol-3-one.
`
`5
`
`12. The use according to claim 10 wherein the MTP inhibiting compound is
`(+)-phenyl-(4-{4-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperidin-
`1-yl)-acetic acid methyl ester.
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`Figure 1 : Plasma CCK (pMol/I) expressed as the median value per group just before
`the meal and 12 and 24 hours after the meal. Dosing of the MTP inhibitor
`"compound A" was done together with the meal which consisted of a liquid
`meal given orally by gavage.
`
`Postprandial CCK (mean+ Stdev) after a single dose in
`dogs
`
`70.0 - . - - - - - - - - - - - - - - - - - - - - - - - - - - - .
`
`60.0 -1----------,___,----------I
`
`~ 50.0 -+ - - - - - - - - - - - - l r - -** - - - - - - - - - - - -1 --vehicle
`:!E 40.0 -1------------~-~--------------1
`I
`--
`• • · .... 0.15 mg/kg
`c..
`__
`--
`~ 3o.o
`__
`8 20.0
`~ 0.63 mg/kg
`- - -
`**
`- - -
`............ T .......•. -----... ....
`,..-
`1 o .0 +------+;:--;;-,..........:....:....:.===,...J,....=::::-=--~----.__.. -~---~ n=8/group
`0.0 -+-----------------------< ** =
`pre
`24
`12
`hour
`
`-
`
`-
`
`-
`
`10
`
`Postprandial CCK (median) after a single dose in dogs
`
`-
`
`45.0
`40.0
`35.0
`~ 30.0
`~ 25.0
`~ 20.0
`u 15.0
`u
`10.0
`5.0
`0.0
`
`/
`
`/
`
`/
`
`/
`
`/
`
`,,
`-
`
`_ /
`
`. -
`
`-. -
`
`---
`
`**
`'
`
`'
`
`/
`
`,
`
`/
`
`--.......... -
`- **
`
`"
`'
`'
`'
`'
`'
`'-
`----~
`
`'
`
`-
`
`pre
`
`12
`hour
`
`24
`
`--vehicle
`- - - - - 0.15 mg/kg
`-
`-
`- 0.63 mg/kg
`
`n=8/group
`** = p<0.01
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`Figure 2 : Postprandial Plasma PYY (pMol/I) levels after 0.02% (w/w) administration
`of the MTP inhibitor "compound A" mixed in diet containing 17 .5% (w/w) fat
`
`5
`
`-::::
`0
`a. -J!!.
`E
`CL> > CL>
`~ a.
`ca
`E
`""
`ca
`a.
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`DARK PHASE
`
`LIGHT PHASE
`
`0
`
`2
`
`4
`
`6
`
`8
`
`1 0
`
`12
`
`14
`
`16
`
`18
`
`20
`
`22
`
`24
`
`Time (hours)
`
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`Figure 3 : Postprandial Plasma GLP-1 (pg/I) levels after 0.02% (w/w) administration
`of the MTP inhibitor "compound A" mixed in diet containing 17 .5% (w/w) fat
`
`5
`
`E
`
`-
`-C> a.
`-"' a;
`
`>
`
`Cl.)
`
`'I"""
`I
`
`a..
`...J
`(!)
`ca
`E
`"' ca
`a..
`
`110
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`Vehicle
`- -• - - MTP
`
`---
`
`DARK PHASE
`
`LIGHT PHASE
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`12
`14
`Time (hours)
`
`16
`
`18
`
`20
`
`22
`
`24
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