AU2002244860A1 - Treatment of type 2 diabetes with inhibitors of dipeptidyl peptidase IV - Google Patents

Treatment of type 2 diabetes with inhibitors of dipeptidyl peptidase IV

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AU2002244860A1
AU2002244860A1 AU2002244860A AU2002244860A AU2002244860A1 AU 2002244860 A1 AU2002244860 A1 AU 2002244860A1 AU 2002244860 A AU2002244860 A AU 2002244860A AU 2002244860 A AU2002244860 A AU 2002244860A AU 2002244860 A1 AU2002244860 A1 AU 2002244860A1
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inhibitor
dipeptidyl peptidase
het
aminoacyl
general formula
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AU2002244860B2 (en
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Michel L Aubert
Pierre Broqua
Beatrice Sudre
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Ferring BV
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Ferring BV
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Priority claimed from GBGB0109146.1A external-priority patent/GB0109146D0/en
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Description

TREATMENT OF TYPE 2 DIABETES WITH INHIBITORS OF DIPEPTIDYL PEPTIDASE IV
FIELD OF THE INVENTION
The present invention relates to a method for delaying the onset of type 2 diabetes and alleviating the physiological consequences of type 2 diabetes.
BACKGROUND
Diabetes mellitus affects about 5% of the population, and type 2 diabetes, also known as non-insulin dependent diabetes mellitus, accounts for more than 80% of all cases. Type 2 diabetes is particularly prevalent in obese people aged over 40. Complications of type 2 diabetes include retinopathy and nephropathy, and diabetics have a significantly increased chance of suffering cardiovascular disease.
A number of drugs are available for the treatment of type 2 diabetes, but new ones, particularly those acting by novel mechanisms, are still needed. One such class of candidate therapeutic agents comprises inhibitors of dipeptidyl peptidase IV (DP-IV, EC.3.4.14.5). These compounds act, at least in part, by blocking the inactivation of endogenous incretins such as GLP-1 and GIP, resulting in an increased sensitivity to insulin and reduced post-prandial hyperglycaemia. To date, however, these compounds have only been examined as a method for controlling the management of blood glucose levels on an acute basis. The implications of long-term treatment with these compounds have not been considered.
SUMMARY OF THE INVENTION
We have now found that chronic treatment with inhibitors of DP-IV in a standard animal model of type 2 diabetes results in a delay in the development of the disease. Accordingly, one aspect of the present invention is a method of treating individuals at risk of developing type 2 diabetes, or in the early stages thereof, so as to prevent the progression of the disease, which method is to administer to the said individual repeated doses of a pharmaceutical composition comprising an inhibitor of DP-IV. Another aspect of the invention is a pharmaceutical composition for use in such treatment. A third aspect of the present invention is the use of inhibitors of DP-IV to prepare such compositions. DETAILED DESCRIPTION OF THE INVENTION
We have examined the effects of chronic treatment of Zucker Diabetic Fatty (ZDF) rats with inhibitors of DP-IV. The ZDF rat is a well known model for human type 2 diabetes. ZDF rats are hyperphagic, and when fed on a high fat diet they become diabetic, as shown by hyperglycaemia, hypertrigyceridaemia, polydipsia and an increase in circulating free fatty acids. Disease onset is observed at about 8 weeks and the animals are fully diabetic by 11 weeks of age. We found that chronic treatment of ZDF rats with inhibitors of DP-IV leads to a significant delay in the onset of the diabetic state, which indicates that such chronic treatment will be useful in human subjects at risk of developing type 2 diabetes, or in the early stages of the disease.
Accordingly, a first aspect of the present invention is a method of treating an individual at risk of developing type 2 diabetes, or in the early stages thereof, so as to delay the onset and progression of the disease. The treatment comprises the administration to the said individual of repeated doses of an inhibitor of DP-IV.
The assessment that an individual is at risk of developing type 2 diabetes will generally be made by an experienced physician, who will take into consideration such factors as the age and weight (and more specifically the body mass index, BMI) of the individual, as well as any history of diabetes in the individual's family and other risk factors. Similarly, a diagnosis of early-stage type 2 diabetes will be made by an experienced physician on the basis of a number of standard analyses and tests.
The inhibitor of DP-IV may be any compound that inhibits the enzymatic activity of DP-IV at a pharmacologically relevant dose. Suitable compounds can be identified as those that significantly inhibit the enzymatic activity of DP-IV in an in vitro assay at concentrations below 10μM. Particularly suitable compounds are those that inhibit the enzymatic activity of DP-IV at concentrations below 0.1 μM. Such activity can be easily determined by one skilled in the art using one of the published assays. Suitable compounds should in addition preferably be selective, i.e. they should not significantly inhibit other unrelated enzymes at a concentration equal to that at which they inhibit DP-IV, and more preferably they should not inhibit such enzymes at a concentration ten-fold greater, even more preferably one hundred-fold greater, than that at which they significantly inhibit DP-IV. The scope of the present invention extends to the use of prodrugs of DP-IV inhibitors. Prodrugs are well known in the art. A prodrug is a compound that is generally inactive per se, but which is subject to chemical or metabolic modification after administration, which modification causes the release of the active pharmaceutical agent. Prodrugs are typically used to increase oral bioavailability or to prolong the duration of action of a compound.
Examples of suitable compounds and methods for their preparation are disclosed in, for example, International Patent Applications WO91/16339, WO93/08259, WO95/15309, WO98/19998, WO99/46272, WO99/61431, WO99/67278, WO99/67279 and WO01/14318; US patents 5,462,928, 5,543,396, 5,939,560, 6,011 ,155, 6,107,317, 6,110,949, 6,124,305, 6,166,063 and 6,201,132; and European patent applications 0 528 858, 0 610 317, 0 731 789, 1 043 328, 1 050 540 and 1 082 314.
In a preferred embodiment of the present invention, the inhibitor of DP-IV is an α- aminoacyl pyrrolidide, an α-aminoacyl thiazolidide, an α-aminoacyl pyrrolidinenitrile, or an α-aminoacyl thiazolidinenitrile. In a more preferred embodiment, the inhibitor of DP-IV is a compound according to general formula 1 or general formula 2, or a pharmaceutically acceptable salt of either of these.
1 2
In these general formulae, X is selected from a methylene group CH2 and a sulphur atom S; R1 is selected from C-i - C6 alkyl groups, including branched and cyclic alkyl groups, and (CH2)nR3; R2 is selected from a hydrogen atom H and a nitrile group ON; R3 is selected from NH-Het and NHCO-Het; Het is a pyridyl, pyrimidyl or pyrazinyl group that is optionally substituted with up to two groups independently selected from methyl, Cl, F, CN.and CF3; and n is 2, 3, 4 or 5.
The compounds according to general formulae 1 and 2 all have at least one basic nitrogen atom and so are able to form addition salts with protic acids. Examples of such acids include hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, fumaric acid, maleic acid, citric acid, benzoic acid, pamoic acid and methanesulphonic acid. Insofar as these acids are pharmaceutically acceptable, such salts are included within the scope of the present invention.
The compounds according to general formula 1 have a stereogenic centre (asymmetric carbon atom) in the aminoacyl group. When R2 is a nitrite, the compounds according to both general formulae have a stereogenic centre in the five-membered ring. Accordingly, these compounds can exist as optical isomers such as enantiomers and diastereomers. All such isomers are included within the scope of the present invention. The preferred stereochemistry is that illustrated in general formulae 3 and 4.
In a preferred embodiment of the present invention, the inhibitor is a compound according to general formula 1. More preferably, it is a compound according to general formula 1 wherein R1 is a C4 branched alkyl group such as sec-butyl or tert-butyl. Most preferably it is such a compound wherein X is CH2 and R2 is a nitrile, or X is S and R2 is H.
In another preferred embodiment of the present invention, the inhibitor is a compound according to general formula 2. More preferably, it is a compound according to general formula 2 wherein R1 is (CH2)nR3, n is 2 and R3 is NH-Het. Most preferably it is such a compound wherein X is CH2, R2 is a nitrile, and Het is 5-cyano-2-pyridyl.
in the method of treatment according to the present invention, the inhibitor of DP-IV will be administered to the individual as a pharmaceutical composition such as, for example, a tablet, capsule, powder, suppository, solution or suspension. The general principles for the preparation of such formulations are well known in the art. The formulation may further comprise such pharmaceutically acceptable excipients as bulking agents, binding agents, preservatives, solvents, flavoring agents and the like. It may further include one or more additional pharmacologically active agents, such as anti-diabetic agents, but preferably the DP-IV inhibitor is the sole active agent. The formulation may be administered by any appropriate route, including oral, buccal, sublingual, rectal, intravaginal and transdermal administration as well as by intravenous, subcutaneous and intramuscular injection. Preferably the formulation is administered orally as a tablet or capsule.
The dose will be determined by the attending physician, taking into consideration all the relevant factors. Typically a single dose will comprise between 1mg and 1000mg, preferably between 5mg and 250mg. The dose may be given once per day or more often, such as twice or three times per day. Treatment will be continued for an extended period of time such as several weeks, months or even years.
Alternatively, the formulation may be administered as a depot which releases active compound over a period of between one week and three months. Such controlled-release formulations are known in the art, and generally comprise a pharmaceutically active species associated with a biocompatible polymer. The polymer may simply encapsulate the active agent, forming a physical barrier to its release into the general circulation, or there may be a chemical association, such as a covalent or ionic interaction, between the polymer and the active agent. Such formulations are generally administered by intramuscular or subcutaneous injection. In this case, the administration will be repeated at intervals of one week up to three months so as to maintain treatment over an extended period.
A second aspect of the present invention is a pharmaceutical composition for the treatment of a person at risk of developing type 2 diabetes, or in the early stages thereof, so as to delay or prevent the progression of the disease. The composition comprises an inhibitor of DP-IV as described above, suitably formulated, together with instructions for repeated dosing.
A third aspect of the present invention is the use of an inhibitor of DP-IV for the preparation of a pharmaceutical composition for the treatment of a person at risk of developing type 2 diabetes, or in the early stages thereof, so as to delay or prevent the progression of the disease. EXAMPLES
Example 1 - Preparation of inhibitors of DP-IV
Inhibitors of DP-IV can be prepared according to published methods.
Example 1 A - (2S)-1-((2'S)-2'-amino-3',3'- imethylbutanoyl)pyrrolidine-2-carbonitrile hydrochloride
The title compound is prepared according to the methods of WO95/15309, and particularly of Example 13 therein. Briefly, BOC-protected tert-butylglycine is coupled to prolineamide, the primary amide function is dehydrated with trifluoroacetic anhydride to give the nitrile, and the BOC-group is removed with HCI in dioxan.
Example 1B - (2S)-1-((2'S)-2'-amino-5'-pyrazιnecarbonyIaminopentanoyl)pyrrolidine- 2-carbonitrile trifluoroacetate
The title compound is prepared according to the method of Example 1A above. Briefly, Nα-BOC-protected Nω-pyrazinecabonylomithine is coupled to prolineamide, the primary amide function is dehydrated with trifluoroacetic anhydride to give the nitrile, and the BOC- group is removed with trifluoroacetic acid. Example 1C - N-lsoleucylthiazolidine hydrochloride
The title compound is prepared according to the standard methods. Briefly, BOC- protected isoleucine is coupled to thiazolidine and the BOC-group is removed with HCl in dioxan.
Example 1D - (2S)-1-((2'-(5"-Cyano-2"-pyridylamino)ethylamino)acetyl)pyrrolidine-2- carbonitrile
The title compound is prepared according to the methods of WO98/19998, and particularly of Example 3 therein. Briefly, bromoacetyl bromide is reacted with prolineamide and the product is dehydrated with trifluoroacetic anhydride to give N-bromoacetylpyrrolidine-2- carbonitrile. This is treated with 2-(5-cyano-2-pyridylamino)ethylamine to give the product.
Example 2 - inhibition of DP-IV in vitro
The in vitro inhibitory action of the compounds is determined in a fluorimetric assay. Human DP-IV is incubated with a standard substrate, Ala-Pro-AFC, in the presence of various concentrations of the inhibitor. The reaction is monitored by measuring the increase in fluorescence due to the reaction product, AFC. Using standard manipulations, an inhibitory constant, Kj, is determined. Typical results are given below.
of Example No. Kι (nM)
1A 1.0
1B 0.4
1C 33.0
1D 5.0 Example 3 - Effect of long-term inhibition of DP-IV in ZDF rat
Male ZDF rats, aged 6.5 weeks at the beginning of the study (day 0), are given the compound of Example 1A (10mg/kg p.o.) once or twice per day for four weeks. Control animals are given vehicle. A group of untreated lean rats is used as a comparison. Glycaemia, insulinaemia, body weight, food and water intake, and plasma triglyceride and free fatty acid levels are monitored throughout the study.
Example 3A - Glycaemia
At the start of the study glycaemia is not significantly different in the obese animals compared to the lean rats. At day 8, the obese control group develop hyperglycaemia, which increases and reaches a plateau by day 19. The animals treated once daily with the inhibitor do not develop significant hyperglycaemia until day 15, and those treated twice daily do not develop significant hyperglycaemia until day 24. The results are presented in Figure 1.
Example 3B - Insulinaemia
All three groups of obese animals show elevated plasma insulin concentrations at the beginning of the study period. In the control obese animal group, the insulin concentration rises rapidly to reach a peak by day 8 before decreasing as the islet β-cells die. In the group treated once daily with the inhibitor a similar pattern is observed, but the peak insulin level is only reached on day 11. In the group treated twice daily with the inhibitor insulin concentration does not attain the same high level, and there is evidence of β-cell survival at the end of the study period. The results are presented in Figure 2.
Example 3C - Body weight gain
All three groups of obese animals gain weight faster than the lean group, but the group treated twice daily with the inhibitor gain less weight than the control obese group and the group treated once daily. The results are presented in Figure 3.
Example 3D - Food and water intake
All three groups of obese animals eat more than the lean group, but from day 17 the food intake for the group treated twice daily is significantly less than that for the control obese group and the once-daily treatment group. From day 10, the control and once-daily treatment groups show an increase in their water consumption, but the twice-daily treatment group maintains a normal water intake. The results are presented in Figures 4 and 5.
Example 3E - Plasma free fatty acid and triglyceride levels
Plasma free fatty acid and triglyceride levels are significantly elevated in the obese animals at day 0, and in control obese animals they increase throughout the study period. Once- daily, and particularly twice-daily treatment attenuates this increase. The results are presented in Figures 6 and 7.
The results described above clearly indicate that long-term inhibition of DP-IV is effective in delaying the onset of diabetic symptoms in the ZDF rat, and hence that inhibitors of DP- IV should be useful as prophylactic agents for people at risk of developing type 2 diabetes and as a treatment for people in the early stages of the disease to delay the progression of diabetic complications.

Claims (1)

  1. 1 A method of treating an individual at risk of developing type 2 diabetes, or in the early stages thereof, so as to delay the onset and progression of the disease, which comprises the administration to the individual of repeated doses of an inhibitor of dipeptidyl peptidase IV or a prodrug thereof.
    2 A method according to Claim 1 in which each dose of inhibitor of dipeptidyl peptidase IV or prodrug thereof is released over a period of between one week and three months.
    3 A method according to Claim 1 or 2 in which each dose is a depot formulation.
    4 A method according to Claim 1 , 2 or 3 in which the repeated doses maintain the treatment over an extended period.
    5 A method according to any preceding claim in which the inhibitor of dipeptidyl peptidase IV is an α-aminoacyl pyrrolidide, an α-aminoacyl thiazolidide, an α-aminoacyl pyrrolidinenitrile or an α-aminoacyl thiazolidinenitrile.
    6 A method according to any preceding claim in which the inhibitor of dipeptidyl peptidase IV is a compound according to general formula 1 or general formula 2 , or a pharmaceutically acceptable salt thereof
    1 2
    wherein: X is selected from CH2 and S;
    R1 is selected from C. - C6 alkyl and (CH2)n) R3;
    R2 is selected from H and CN;
    R3 is selected from NH-Het and NHCO-Het; and
    Het is a pyridyl, pyrimidyl or pyrazinyl group that is optionally substituted with up to two groups independently selected from methyl, Cl, F, CN and CF3; and n is 2, 3, 4 or 5.
    A method according to any preceding claim in which the inhibitor of dipeptidyl peptidase IV is a compound according to general formula 1 or a pharmaceutically acceptable salt thereof wherein R1 is C4 alkyl.
    A method according to any of claims 1 to 6 in which the inhibitor of dipeptidyl peptidase IV is a compound according to general formula 2, or a pharmaceutically acceptable salt thereof, wherein X is CH2, R2 is CN, R3 is NH-Het, Het is a 5-cyano-2-pyridyl group, and n is 2.
    A pharmaceutical composition for treating an individual at risk of developing type 2 diabetes, or in the early stages thereof, so as to delay the onset and progression of the disease, comprising an inhibitor of dipeptidyl peptidase IV or a prodrug thereof.
    A composition according to claim 9 which releases the inhibitor of dipeptidyl peptidase IV or prodrug thereof over a period of between one week and three months.
    A composition according to Claim 9 or 10 which is a depot formulation.
    A composition according to any of claims 9, 10 or 11 for treating the individual over an extended period.
    A composition according to any of claims 9 to 12 wherein the inhibitor of dipeptidyl peptidase IV is an α-aminoacyl pyrrolidide, an α-aminoacyl thiazolidide, an α-aminoacyl pyrrolidinenitrile or an α-aminoacyl thiazolidinenitrile.
    A composition according to any of claims 9 to 13 wherein the inhibitor of dipeptidyl peptidase IV is a compound according to general formula 1 or general formula 2 , or a pharmaceutically acceptable salt thereof
    wherein: X is selected from CH2 and S;
    R1 is selected from C^ - C6 alkyl and (CH2)n) R3;
    R2 is selected from H and CN;
    R3 is selected from NH-Het and NHCO-Het; and
    Het is a pyridyl, pyrimidyl or pyrazinyl group that is optionally substituted with up to two groups independently selected from methyl, Cl, F, CN and CF3; and n is 2, 3, 4 or 5.
    A composition according to any of claims 9 to 14 wherein the inhibitor of dipeptidyl peptidase IV is a compound according to general formula 1 or a pharmaceutically acceptable salt thereof wherein R1 is C4 alkyl.
    A composition according to any of claims 9 to 14 wherein the inhibitor of dipeptidyl peptidase IV is a compound according to general formula 2, or a pharmaceutically acceptable salt thereof, wherein X is CH2, R2 is CN, R3 is NH-Het, Het is a 5-cyano-2-pyridyl group, and n is 2.
    The use of an inhibitor of dipeptidyl peptidase IV or a prodrug thereof for the preparation of a medicament for treating an individual at risk of developing type 2 diabetes, or in the early stages thereof, so as to delay the onset and progression of the disease.
    The use according to claim 17 wherein the medicament releases the inhibitor of dipeptidyl peptidase IV or prodrug thereof over a period of between one week and three months.
    The use according to claim 18 wherein the medicament is a depot formulation. The use according to any of claims 17, 18 or 19 wherein the medicament is for treatment of the individual over an extended period.
    The use according to any of claims 17 to 20 in which the inhibitor of dipeptidyl peptidase IV is an α-aminoacyl pyrrolidide, an α-aminoacyl thiazolidide, an α-aminoacyl pyrrolidinenitrile or an α-aminoacyl thiazolidinenitrile.
    The use according to any of claims 17 to 21 in which the inhibitor of dipeptidyl peptidase IV is a compound according to general formula 1 or general formula 2 , or a pharmaceutically acceptable salt thereof
    wherein: X is selected from CH2 and S;
    R1 is selected from d - C6 alkyl and (CH2)n) R3;
    R2 is selected from H and CN;
    R3 is selected from NH-Het and NHCO-Het; and
    Het is a pyridyl, pyrimidyl or pyrazinyl group that is optionally substituted with up to two groups independently selected from methyl, Cl, F, CN and CF3; and n is 2, 3, 4 or 5.
    The use according to any of claims 17 to 22 in which the inhibitor of dipeptidyl peptidase IV is a compound according to general formula 1 or a pharmaceutically acceptable salt thereof wherein R1 is C4 alkyl.
    The use according to any of claims 17 to 22 in which the inhibitor of dipeptidyl peptidase IV is a compound according to general formula 2, or a pharmaceutically acceptable salt thereof, wherein X is CH2, R2 is CN, R3 is NH-Het, Het is a 5-cyano-2-pyridyl group, and n is 2. The use of an inhibitor of dipeptidyl peptidase IV or a prodrug thereof for the preparation of a pharmaceutical composition for repeatedly treating an individual at risk of developing type 2 diabetes, or in the early stages thereof, so as to delay the onset and progression of the disease.
    The use according to claim 25 for the preparation of a pharmaceutical composition which releases the inhibitor of dipeptidyl peptidase IV or prodrug thereof over a period of between one week and three months.
    The use according to claim 25 or 26 in which the pharmaceutical composition is a depot formulation.
    A method of treating an individual at risk of developing type 2 diabetes, or in the early stages thereof, so as to delay the onset and progression of the disease, which comprises the administration to the individual of a depot formulation of an inhibitor of dipeptidyl peptidase IV or a prodrug thereof.
    A method according to Claim 28 in which the depot formulation releases the inhibitor of dipeptidyl peptidase IV or prodrug thereof over a period of between one week and three months.
    A method according to Claim 28 or 29 in which repeated doses of the depot formulation are administered to maintain the treatment over an extended period.
AU2002244860A 2001-04-11 2002-04-10 Treatment of type 2 diabetes with inhibitors of dipeptidyl peptidase IV Ceased AU2002244860B2 (en)

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GB0109146.1 2001-04-11
GBGB0109146.1A GB0109146D0 (en) 2001-04-11 2001-04-11 Treatment of type 2 diabetes
PCT/GB2002/001674 WO2002083109A1 (en) 2001-04-11 2002-04-10 Treatment of type 2 diabetes with inhibitors of dipeptidyl peptidase iv

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Families Citing this family (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20040015298A (en) 2001-06-27 2004-02-18 스미스클라인 비참 코포레이션 Fluoropyrrolidines as dipeptidyl peptidase inhibitors
GB0125445D0 (en) * 2001-10-23 2001-12-12 Ferring Bv Protease Inhibitors
AU2002952946A0 (en) * 2002-11-27 2002-12-12 Fujisawa Pharmaceutical Co., Ltd. Dpp-iv inhibitor
US7550590B2 (en) 2003-03-25 2009-06-23 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
US6995183B2 (en) 2003-08-01 2006-02-07 Bristol Myers Squibb Company Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
US7678909B1 (en) 2003-08-13 2010-03-16 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
ZA200602051B (en) 2003-08-13 2007-10-31 Takeda Pharmaceutical 4-pyrimidone derivatives and their use as peptidyl peptidase inhibitors
US7169926B1 (en) 2003-08-13 2007-01-30 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
WO2005026148A1 (en) 2003-09-08 2005-03-24 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
KR20170005163A (en) 2003-11-17 2017-01-11 노파르티스 아게 Use of dipeptidyl peptidase iv inhibitors
US20070149451A1 (en) * 2003-11-17 2007-06-28 Holmes David G Combination of a dpp IV inhibitor and an antiobesity or appetite regulating agent
EP2165703A3 (en) 2004-01-20 2012-03-28 Novartis Pharma AG Direct compression formulation and process
US7732446B1 (en) 2004-03-11 2010-06-08 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
CN102127053A (en) 2004-03-15 2011-07-20 武田药品工业株式会社 Dipeptidyl peptidase inhibitors
US7687638B2 (en) 2004-06-04 2010-03-30 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
WO2006019965A2 (en) 2004-07-16 2006-02-23 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
ATE553077T1 (en) 2004-07-23 2012-04-15 Nuada Llc PEPTIDATE INHIBITORS
US7872124B2 (en) 2004-12-21 2011-01-18 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
DOP2006000008A (en) 2005-01-10 2006-08-31 Arena Pharm Inc COMBINED THERAPY FOR THE TREATMENT OF DIABETES AND RELATED AFFECTIONS AND FOR THE TREATMENT OF AFFECTIONS THAT IMPROVE THROUGH AN INCREASE IN THE BLOOD CONCENTRATION OF GLP-1
AU2006239929B2 (en) 2005-04-22 2011-11-03 Alantos Pharmaceuticals Holding, Inc. Dipeptidyl peptidase-IV inhibitors
CN101232873A (en) * 2005-08-11 2008-07-30 霍夫曼-拉罗奇有限公司 Pharmaceutical composition comprising a dpp-iv inhibitor
DK1942898T4 (en) 2005-09-14 2014-06-02 Takeda Pharmaceutical Dipeptidyl peptidase inhibitors for the treatment of diabetes
KR101368988B1 (en) 2005-09-16 2014-02-28 다케다 야쿠힌 고교 가부시키가이샤 Dipeptidyl peptidase inhibitors
GB0526291D0 (en) 2005-12-23 2006-02-01 Prosidion Ltd Therapeutic method
WO2007112347A1 (en) 2006-03-28 2007-10-04 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
PE20071221A1 (en) 2006-04-11 2007-12-14 Arena Pharm Inc GPR119 RECEPTOR AGONISTS IN METHODS TO INCREASE BONE MASS AND TO TREAT OSTEOPOROSIS AND OTHER CONDITIONS CHARACTERIZED BY LOW BONE MASS, AND COMBINED THERAPY RELATED TO THESE AGONISTS
US8324383B2 (en) 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
TW200838536A (en) 2006-11-29 2008-10-01 Takeda Pharmaceutical Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US8093236B2 (en) 2007-03-13 2012-01-10 Takeda Pharmaceuticals Company Limited Weekly administration of dipeptidyl peptidase inhibitors
EP2146210A1 (en) 2008-04-07 2010-01-20 Arena Pharmaceuticals, Inc. Methods of using A G protein-coupled receptor to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY
FR2938999B1 (en) * 2008-11-24 2011-07-01 Oreal METHOD OF PREPARING A FRAGRANCE WITHIN A SYSTEM COMPRISING A PLURALITY OF INTERACTIVE PERFUME FORMULATION TERMINALS AND A AGENCY SERVER FOR EXCHANGING DATA WITH THE PLURALITY OF TERMINALS
AR077642A1 (en) 2009-07-09 2011-09-14 Arena Pharm Inc METABOLISM MODULATORS AND THE TREATMENT OF DISORDERS RELATED TO THE SAME
CN102918027A (en) 2010-04-06 2013-02-06 艾尼纳制药公司 Modulators of the gpr119 receptor and the treatment of disorders related thereto
BR112013008100A2 (en) 2010-09-22 2016-08-09 Arena Pharm Inc "gpr19 receptor modulators and the treatment of disorders related thereto."
WO2012135570A1 (en) 2011-04-01 2012-10-04 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
US20140066369A1 (en) 2011-04-19 2014-03-06 Arena Pharmaceuticals, Inc. Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto
US20140051714A1 (en) 2011-04-22 2014-02-20 Arena Pharmaceuticals, Inc. Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto
US20140038889A1 (en) 2011-04-22 2014-02-06 Arena Pharmaceuticals, Inc. Modulators Of The GPR119 Receptor And The Treatment Of Disorders Related Thereto
WO2012170702A1 (en) 2011-06-08 2012-12-13 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2013055910A1 (en) 2011-10-12 2013-04-18 Arena Pharmaceuticals, Inc. Modulators of the gpr119 receptor and the treatment of disorders related thereto
WO2014074668A1 (en) 2012-11-08 2014-05-15 Arena Pharmaceuticals, Inc. Modulators of gpr119 and the treatment of disorders related thereto
GB201415598D0 (en) 2014-09-03 2014-10-15 Univ Birmingham Elavated Itercranial Pressure Treatment
AU2016229982B2 (en) 2015-03-09 2020-06-18 Intekrin Therapeutics, Inc. Methods for the treatment of nonalcoholic fatty liver disease and/or lipodystrophy
WO2018162722A1 (en) 2017-03-09 2018-09-13 Deutsches Institut Für Ernährungsforschung Potsdam-Rehbrücke Dpp-4 inhibitors for use in treating bone fractures
EP3606527A1 (en) 2017-04-03 2020-02-12 Coherus Biosciences, Inc. Ppar-gamma agonist for treatment of progressive supranuclear palsy

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL111785A0 (en) * 1993-12-03 1995-01-24 Ferring Bv Dp-iv inhibitors and pharmaceutical compositions containing them
DE19616486C5 (en) * 1996-04-25 2016-06-30 Royalty Pharma Collection Trust Method for lowering the blood glucose level in mammals
US6011155A (en) * 1996-11-07 2000-01-04 Novartis Ag N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
DE19823831A1 (en) * 1998-05-28 1999-12-02 Probiodrug Ges Fuer Arzneim New pharmaceutical use of isoleucyl thiazolidide and its salts
CO5150173A1 (en) * 1998-12-10 2002-04-29 Novartis Ag COMPOUNDS N- (REPLACED GLYCLE) -2-DIPEPTIDYL-IV PEPTIDASE INHIBITING CYANOPIRROLIDINS (DPP-IV) WHICH ARE EFFECTIVE IN THE TREATMENT OF CONDITIONS MEDIATED BY DPP-IV INHIBITION
ES2353728T3 (en) * 1999-02-10 2011-03-04 Curis, Inc. PEPTIDE YY (PYY) TO TREAT METABOLIC DISORDERS OF GLUCOSE.
GB9906714D0 (en) * 1999-03-23 1999-05-19 Ferring Bv Compositions for improving fertility
US6110949A (en) * 1999-06-24 2000-08-29 Novartis Ag N-(substituted glycyl)-4-cyanothiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
US6107317A (en) * 1999-06-24 2000-08-22 Novartis Ag N-(substituted glycyl)-thiazolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV
AU1916401A (en) * 1999-11-12 2001-06-06 Guilford Pharmaceuticals Inc. Dipeptidyl peptidase iv inhibitors and methods of making and using dipeptidyl peptidase iv inhibitors
GB9928330D0 (en) * 1999-11-30 2000-01-26 Ferring Bv Novel antidiabetic agents
DE60137216D1 (en) * 2000-03-31 2009-02-12 Prosidion Ltd IMPROVING THE ACTIVITY OF THE ISLAND CELLS IN DIABETES MELLITUS AND ITS PREVENTION
GB0010188D0 (en) * 2000-04-26 2000-06-14 Ferring Bv Inhibitors of dipeptidyl peptidase IV
GB0014969D0 (en) * 2000-06-19 2000-08-09 Smithkline Beecham Plc Novel method of treatment

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