WO1999065941A1 - Insulin analogue - Google Patents
Insulin analogue Download PDFInfo
- Publication number
- WO1999065941A1 WO1999065941A1 PCT/GB1998/001722 GB9801722W WO9965941A1 WO 1999065941 A1 WO1999065941 A1 WO 1999065941A1 GB 9801722 W GB9801722 W GB 9801722W WO 9965941 A1 WO9965941 A1 WO 9965941A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- insulin
- ins
- binding
- compound according
- human
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/62—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to novel insulin analogues which are covalent conjugates of an insulin molecule and a derivative of the hormone thyroxine, 3,3' ,5' triiodothyronine .
- T4 thyroxine binding proteins
- T4-insulin conjugate may retain thyroxine activity.
- the present invention seeks to solve this problem while providing a conjugate which retains its hepatoselectivity, insulin activity and circulating protein affinity.
- a new compound according to the invention comprises an insulin molecule covalently bound to 3,3',5'- triiodothyronine .
- the 3 , 3 ' , 5 ' triiodothyronine molecule is not a naturally occurring compound. It is an isomer of 3,5,3' triiodothyronine (T3) and is consequently known as reverse T3 , rT3. It has insignificant activity on thyroxine receptor, but thyroxine binding proteins have an affinity for the molecule. Thus the compound of the invention should have affinity for TBP's and, it is believed, consequential hepatoselectivity whilst the compound and its metabolites should not stimulate thyroxine activity.
- the rT3 moiety should be conjugated to a residue of the insulin molecule such that insulin activity is not adversely affected. As in O-A-95/05187, conjugation is preferably through the Bl residue of insulin. Alternatively the B29 residue may be linked to rT3. In O- 95/07931, the B29 residue may be derivatised and the methods of conjugating a carboxylic acid-containing compound to the B29 residue as disclosed in that reference may be used in the present invention.
- the insulin may be made by recombinant DNA techniques or may be isolated from natural sources, human or animal. Recombinant insulin may have deleted residues as desired, for instance the B29 residue may be deleted. Other residues of naturally occurring insulin may be substituted, usually by conservative substitutions. For instance in WO- A-95/07931, analogues in which the B3 and/or A21 residues are other than those of naturally occurring insulin.
- the rT3 molecule is conjugated to the insulin using conventional biochemical techniques in which pendant groups on the appropriate residue of the insulin molecule are covalently bonded to rT3 , through the carboxylate group. The pendant group is usually the e-amino group of a lysine residue. Any other lysine residues may be rendered unreactive by protecting the e-amine groups using conventional techniques. Protecting groups are removed after conjugation to the rT3 molecule.
- the phenolic OH group of rT3 is protected during the process, also. Either or both of the amine group and the carboxylate group may be activated prior to contact of the insulin with the rT3. Conventional techniques for generation of amide linkages may be used, for instance using known reagents.
- a spacer may be included between the insulin molecule and the rT3 molecule.
- a spacer may, for instance, improve retention of insulin activity and/or TBP-binding.
- a spacer may also be used to control in vivo cleavage and metabolism of the conjugate compound, and consequently its insulin activity.
- a spacer may, for instance include a chain comprising 2 to 22 carbon and/or heteroatoms, such as a 4- 10 atom chain, preferably comprising an alkylene group and carbonyl and/or amino groups, amido groups and or oxygen atoms in ester or ether linkages.
- the insulin-rT3 conjugate has a similar potency relative to human insulin itself. This is in contrast to T4-insulin, which appears to have a greater potency than human insulin. In the presence of binding proteins, especially thyroxin binding proteins, the potency of T4-insulin is reduced, whereas these proteins do not affect the potency of rT3 -insulin. These data indicate that the conjugate is likely to have similar effects as insulin in vivo .
- the novel compound is suitable for use in a method of treatment of the human or animal , for instance to replace insulin in a method of insulin replacement therapy.
- the invention thus comprehends novel compositions containing the compound as well as pharmaceutical compositions containing the compound and a pharmaceutically acceptable excipient .
- the composition is formulated so as to be suitable for administration by the usual routes, generally by subcutaneous injection. Accordingly the carrier is generally aqueous.
- the invention comprehends also a new use of the compound in the manufacture of a medicament for use in a method of treatment of the human or animal body.
- the protein material was diluted in a mixture of 1 ml dimethylformamide, 1.5 ml methanol and 1.5 ml water. The solution was cooled to 0°C and addition of 0.5 ml of ice-cold 2 M sodium hydroxide solution started the cleavage reaction. The reaction was stopped by acidification with 1 ml of 10% (v/v) acetic acid. The protein was precipitated by pipetting the reaction solution into a mixture of 250 ml of ice-cold ether and 20 ml methanol and stirring for 1 h. The ether was decantated from the precipitated protein and the protein dried in vacuo .
- the rT3 -insulin conjugate made in Example 1 is used in various tests to determine the binding potencies of the analogues on liver plasma membrane.
- 125 -Insulin is used as the labelled insulin. It is known that insulin itself inhibits binding of 125 -Insulin.
- THBP does not appear to affect the ability of H-Ins to inhibit the binding of 125 -Insulin to insulin receptors on LPM.
- THBP does not appear to affect the ability of rT3-Ins to inhibit the binding of 125 -Insulin to insulin receptors on LPM.
- TBG seems to have the greatest effect on T4-Ins, i.e. causes the greatest shift.
- the ED50's as calculated by the G-PIP software were inverse logged because the concentrations entered in G-PIP had to be entered as the log of the concentrations. The average (nmol/l)+ SEM of the ED50's was then calculated. The results are shown in Table 1. These give a quantitative idea of the shift, if any in the equilibrium binding curves .
- the Scatchard plot of H-Ins demonstrates the characteristic curvilinear shape of negative co-operativity that should be exhibited by human insulin. It may be seen from the Scatchard plots of rT3-Ins and T4-Ins that these analogues also exhibit negative co-operativity due to their curvilinear shape.
- T4 insulin is Bl-thyroxyl-insulin made according to the technique described in WO-A-95/05187 , Example 1.
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000554766A JP2002518408A (en) | 1998-06-12 | 1998-06-12 | Insulin analogues |
EP98928469A EP1086130A1 (en) | 1998-06-12 | 1998-06-12 | Insulin analogue |
CA002334859A CA2334859A1 (en) | 1998-06-12 | 1998-06-12 | Insulin analogue |
AU80297/98A AU8029798A (en) | 1998-06-12 | 1998-06-12 | Insulin analogue |
PCT/GB1998/001722 WO1999065941A1 (en) | 1998-06-12 | 1998-06-12 | Insulin analogue |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/GB1998/001722 WO1999065941A1 (en) | 1998-06-12 | 1998-06-12 | Insulin analogue |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999065941A1 true WO1999065941A1 (en) | 1999-12-23 |
Family
ID=10825972
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1998/001722 WO1999065941A1 (en) | 1998-06-12 | 1998-06-12 | Insulin analogue |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1086130A1 (en) |
JP (1) | JP2002518408A (en) |
AU (1) | AU8029798A (en) |
CA (1) | CA2334859A1 (en) |
WO (1) | WO1999065941A1 (en) |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002004515A1 (en) * | 2000-07-10 | 2002-01-17 | Btg International Limited | Insulin derivatives and synthesis thereof |
US6828297B2 (en) | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of insulin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
US6828305B2 (en) | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of growth hormone drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
USRE39055E1 (en) | 1993-08-13 | 2006-04-04 | Btg International Limited | Hepatoselective pharmaceutical actives |
JP2007520441A (en) * | 2003-07-25 | 2007-07-26 | コンジュシェム,インコーポレイティド | Persistent insulin derivatives and methods thereof |
WO2007096431A1 (en) * | 2006-02-27 | 2007-08-30 | Novo Nordisk A/S | Insulin derivatives |
CN1964989B (en) * | 2003-07-25 | 2012-02-01 | 康久化学生物技术公司 | Long lasting insulin derivatives and methods thereof |
US8710001B2 (en) | 2006-07-31 | 2014-04-29 | Novo Nordisk A/S | PEGylated, extended insulins |
US9018161B2 (en) | 2006-09-22 | 2015-04-28 | Novo Nordisk A/S | Protease resistant insulin analogues |
US9260502B2 (en) | 2008-03-14 | 2016-02-16 | Novo Nordisk A/S | Protease-stabilized insulin analogues |
US9387176B2 (en) | 2007-04-30 | 2016-07-12 | Novo Nordisk A/S | Method for drying a protein composition, a dried protein composition and a pharmaceutical composition comprising the dried protein |
US9481721B2 (en) | 2012-04-11 | 2016-11-01 | Novo Nordisk A/S | Insulin formulations |
US9688737B2 (en) | 2008-03-18 | 2017-06-27 | Novo Nordisk A/S | Protease stabilized acylated insulin analogues |
US9896496B2 (en) | 2013-10-07 | 2018-02-20 | Novo Nordisk A/S | Derivative of an insulin analogue |
US10040839B2 (en) | 2014-02-28 | 2018-08-07 | Novo Nordisk A/S | Insulin derivatives and the medical uses hereof |
US10265385B2 (en) | 2016-12-16 | 2019-04-23 | Novo Nordisk A/S | Insulin containing pharmaceutical compositions |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995005187A1 (en) * | 1993-08-13 | 1995-02-23 | United Medical & Dental Schools Of Guy's And St Thomas' Hospitals | Hepatoselective pharmaceutical actives |
WO1995007931A1 (en) * | 1993-09-17 | 1995-03-23 | Novo Nordisk A/S | Acylated insulin |
-
1998
- 1998-06-12 WO PCT/GB1998/001722 patent/WO1999065941A1/en not_active Application Discontinuation
- 1998-06-12 EP EP98928469A patent/EP1086130A1/en not_active Withdrawn
- 1998-06-12 CA CA002334859A patent/CA2334859A1/en not_active Abandoned
- 1998-06-12 JP JP2000554766A patent/JP2002518408A/en active Pending
- 1998-06-12 AU AU80297/98A patent/AU8029798A/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995005187A1 (en) * | 1993-08-13 | 1995-02-23 | United Medical & Dental Schools Of Guy's And St Thomas' Hospitals | Hepatoselective pharmaceutical actives |
WO1995007931A1 (en) * | 1993-09-17 | 1995-03-23 | Novo Nordisk A/S | Acylated insulin |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE39055E1 (en) | 1993-08-13 | 2006-04-04 | Btg International Limited | Hepatoselective pharmaceutical actives |
WO2002004515A1 (en) * | 2000-07-10 | 2002-01-17 | Btg International Limited | Insulin derivatives and synthesis thereof |
US6828297B2 (en) | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of insulin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
US6828305B2 (en) | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of growth hormone drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
CN1964989B (en) * | 2003-07-25 | 2012-02-01 | 康久化学生物技术公司 | Long lasting insulin derivatives and methods thereof |
JP2007520441A (en) * | 2003-07-25 | 2007-07-26 | コンジュシェム,インコーポレイティド | Persistent insulin derivatives and methods thereof |
EP2085406A1 (en) * | 2003-07-25 | 2009-08-05 | ConjuChem Biotechnologies Inc. | Long lasting insulin derivatives and methods thereof |
US8722620B2 (en) | 2006-02-27 | 2014-05-13 | Novo Nordisk A/S | Insulin derivatives |
WO2007096431A1 (en) * | 2006-02-27 | 2007-08-30 | Novo Nordisk A/S | Insulin derivatives |
EP2256129A1 (en) * | 2006-02-27 | 2010-12-01 | Novo Nordisk A/S | Insulin derivatives |
US8710001B2 (en) | 2006-07-31 | 2014-04-29 | Novo Nordisk A/S | PEGylated, extended insulins |
US9018161B2 (en) | 2006-09-22 | 2015-04-28 | Novo Nordisk A/S | Protease resistant insulin analogues |
US9387176B2 (en) | 2007-04-30 | 2016-07-12 | Novo Nordisk A/S | Method for drying a protein composition, a dried protein composition and a pharmaceutical composition comprising the dried protein |
US9260502B2 (en) | 2008-03-14 | 2016-02-16 | Novo Nordisk A/S | Protease-stabilized insulin analogues |
US10259856B2 (en) | 2008-03-18 | 2019-04-16 | Novo Nordisk A/S | Protease stabilized acylated insulin analogues |
US9688737B2 (en) | 2008-03-18 | 2017-06-27 | Novo Nordisk A/S | Protease stabilized acylated insulin analogues |
US9481721B2 (en) | 2012-04-11 | 2016-11-01 | Novo Nordisk A/S | Insulin formulations |
US9896496B2 (en) | 2013-10-07 | 2018-02-20 | Novo Nordisk A/S | Derivative of an insulin analogue |
US10040839B2 (en) | 2014-02-28 | 2018-08-07 | Novo Nordisk A/S | Insulin derivatives and the medical uses hereof |
US10265385B2 (en) | 2016-12-16 | 2019-04-23 | Novo Nordisk A/S | Insulin containing pharmaceutical compositions |
US10596231B2 (en) | 2016-12-16 | 2020-03-24 | Novo Nordisk A/S | Insulin containing pharmaceutical compositions |
Also Published As
Publication number | Publication date |
---|---|
EP1086130A1 (en) | 2001-03-28 |
CA2334859A1 (en) | 1999-12-23 |
JP2002518408A (en) | 2002-06-25 |
AU8029798A (en) | 2000-01-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO1999065941A1 (en) | Insulin analogue | |
EP2718315B1 (en) | Pramlintide derivatives | |
RU2578591C2 (en) | Dipeptide linked medicinal agents | |
JP5977945B2 (en) | Conjugate proteins with long-term in vivo efficacy | |
KR0173478B1 (en) | Parathyroid hormone antagonists | |
JP2848411B2 (en) | Atrial natriuretic peptide clearance inhibitor | |
EP2340261B1 (en) | Amylin derivatives | |
AU720966B2 (en) | Insulin derivatives | |
JP2018123169A (en) | Hepcidin analogs and uses thereof | |
US20130137849A1 (en) | Dipeptide linked medicinal agents | |
JP2000504732A (en) | Insulin derivatives and their use | |
JPH11502204A (en) | Lipophilic peptide hormone derivatives | |
GB2393960A (en) | Erythropoietin analogues conjugated with polyethylene glycol | |
NZ549332A (en) | Amylin family peptides and methods for making and using them | |
IE83655B1 (en) | Synthetic peptides for detoxification of bacterial endotoxins and treatment of septic shock | |
EP1290024A1 (en) | Glucose dependent release of insulin from glucose sensing insulin derivatives | |
JPH085916B2 (en) | New calcitonin derivative | |
HUT69963A (en) | Non-naturally-occuring fusion proteins and process for preparing them | |
JPH06228199A (en) | Peptide binding body capable of passing through blood brain barrier | |
US20050191240A1 (en) | Labeled neurotensin derivatives | |
WO2009156473A1 (en) | Derivatised hybrid peptides of amylin and salmon calcitonin | |
US7851433B2 (en) | Method of purifying TFPI and TFPI analogs | |
US8618049B2 (en) | Ester insulin | |
MXPA97007056A (en) | Insulated derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
ENP | Entry into the national phase |
Ref document number: 2334859 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1998928469 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 09719423 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: 1998928469 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1998928469 Country of ref document: EP |