INSULIN RECEPTOR PARTIAL AGONISTS

• US 20190092833A1
• Filed: 11/26/2018
• Published: 03/28/2019
• Est. Priority Date: 11/21/2014
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Lin, Songnian, Yan, Lin, Huo, Pei, Pissarnitski, Dmitri, Feng, Danqing, Nargund, Ravi, Zhu, Yuping, Kekec, Ahmet, Madsen-Duggan, Christina B., Shi, Zhi-Cai, Wu, Zhicai, Mu, Yingjun
• Granted Patent: US 10,800,827 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/62 Insulins
• CPC Class Codes: C07K 2319/00 Fusion polypeptide

Abstract

Insulin dimers and insulin analog dimers that act as partial agonists at the insulin receptor are disclosed.

Claims

1. An insulin receptor partial agonist comprising:

a first insulin or insulin analog heterodimer and a second insulin or insulin analog heterodimer, each heterodimer including an A-chain polypeptide and a B-chain polypeptide, wherein the A-chain polypeptide and the B-chain polypeptide are linked together through interchain disulfide bonds;

wherein the first and second insulin or insulin analog heterodimers are covalently linked together through a linking moiety joining the side chain of an amino acid at or near the carboxy terminus of the two respective B-chain polypeptides; and

wherein the amino terminus of at least one of the A-chain polypeptides and the B-chain polypeptides is covalently linked to a substituent,

with the proviso that the linking moiety does not include a disulfide bond.

2. The insulin receptor partial agonist of claim 1, wherein the insulin receptor partial agonist comprises a first and second insulin or insulin analog heterodimers are the same or wherein the first and second insulin or insulin analog heterodimers are different.

3. The insulin receptor partial agonist of claim 1, wherein the insulin receptor partial agonists comprises a linking moiety covalently links the first insulin or insulin analog heterodimer and the second insulin or insulin analog heterodimer via the epsilon amino group of a lysine residue at or near the carboxy terminus of their respective B-chain polypeptides.

4. The insulin receptor partial agonist of claim 1, wherein the substituent comprises a general formula RC(O)—

, where R can be R′

CH2, R′

NH, R′

O, and R′

can be H, linear alkyl chain, amino acid, peptide, polyethylene glycol (PEG), and a saccharide.

5. The insulin receptor partial agonist of claim 1, wherein the insulin receptor partial agonist comprises a substituent selected from the group consisting of acetyl, phenylacetyl, carbamoyl, N-alkyl carbamoyl, isobutyl, methoxy acetyl, glycine, aminoethylglucose (AEG), AEG-C6, PEG1, PEG2, N-dimethyl, and alkoxycarbonyl.

6. The insulin receptor partial agonist of claim 1, wherein the insulin receptor partial agonist comprises a first and second insulins or insulin analogs, which are independently selected from the group consisting of native human insulin, insulin lispro, insulin aspart, desB30 insulin, and insulin glargine.

7. The insulin receptor partial agonist of claim 1, wherein each A-chain polypeptide independently comprises the amino acid sequence GX₂X₃EQCCX₈SICSLYQLX₁₇NX₁₉CX₂₃ (SEQ ID NO:

3) and each B-chain polypeptide independently comprises the amino acid sequence X₂₅LCGX₂₉X₃₀LVEALYLVCGERGFX27YTX₃₁X₃₂ (SEQ ID NO;

4) or X₂₂VNQX₂₅X₂₆CGX₂₉X₃₀LVEALYLVCGERGFX₂₇YTX₃₁X₃₂X₃₃X₃₄X₃₅ (SEQ ID NO;

5) wherein X₂ is isoleucine or threonine;

X₃ is valine, glycine, or leucine;

X₈ is threonine or histidine;

X₁₇ is glutamic acid or glutamine;

X₁₉ is tyrosine, 4-methoxy-phenylalanine, alanine, or 4-amino phenylalanine;

X₂₃ is asparagine or glycine;

X₂₂ is or phenylalanine and desamino-phenylalanine;

X₂₅ is histidine or threonine;

X26 is leucine or glycine;

X₂₇ is phenylalanine or aspartic acid;

X₂₉ is alanine, glycine, or serine;

X₃₀ is histidine, aspartic acid, glutamic acid, homocysteic acid, or cysteic acid;

X₃₁ is aspartic acid, proline, or lysine;

X₃₂ is lysine or proline;

X₃₃ is threonine, alanine, or absent;

X₃₄ is arginine or absent; and

X₃₅ is arginine or absent;

with the proviso at least one of X₃₁ or X₃₂ is lysine.

8. The insulin receptor partial agonist of claim 1, wherein the linking moiety comprises a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-C20 hydrocarbon chain wherein one or more methylene units are optionally and independently replaced by —

O—

, —

S—

, —

N(R)—

, —

C(O)—

, C(O)O—

, OC(O)—

, —

N(R)C(O)—

, —

C(O)N(R)—

, —

S(O)—

, —

S(O)₂—

, —

N(R)SO₂—

, SO₂N(R)—

, a heterocyclic group, an aryl group, or a heteroaryl group, wherein each occurrence of R independently comprises hydrogen, a suitable protecting group, an acyl moiety, arylalkyl moiety, aliphatic moiety, aryl moiety, heteroaryl moiety, or heteroaliphatic moiety, and poly(ethylene glycol) (PEG).

9. The insulin receptor partial agonist of claim 1, wherein the linking moiety comprises an alkyldioyl, —

C(O)(CH₂)_nC(O)—

, wherein n=0-4, an acyl moiety, —

C(O)RC(O)—

, where R is alkyl chain, poly(ethylene glycol) (PEG) chain, amide-containing chain, triazole(s)-containing chain, cyclooctyne-containing moiety, a substituted acyl chain, or a polyethylene glycol (PEG) chain.

10. A composition comprising the insulin receptor partial agonist of claim 1 and a pharmaceutically acceptable carrier.

11-73. -73. (canceled)

74. A compound selected from the group consisting of

75. A composition comprising one or more compounds of claim 74 and a pharmaceutically acceptable carrier.

76. A method for treating diabetes comprising administering to an individual with diabetes a therapeutically effective amount of a composition comprising the insulin receptor partial agonist of claim 75.

77. The method of claim 76, wherein the diabetes is Type 1 diabetes, Type 2 diabetes, or gestational diabetes.

78-81. -81. (canceled)

82. An insulin dimer comprising:

(a) a first B29 or B28 Lys of a first insulin heterodimer molecule having a first A-chain polypeptide and first B-chain polypeptide and a second B29 or B28 Lys of a second insulin heterodimer having a second A-chain polypeptide and second B-chain polypeptide conjugated together by a bifunctional linker selected from the group consisting Linker 1, Linker 2, Linker 3, Linker 10, Linker 11, Liner 12, Linker 14, Linker 15, Linker 16, Linker 17, Linker 18, Linker 19, Linker 20, Linker 21, Linker 22, Linker 23, Linker 24, Linker 25, Linker 26, Linker 27, Linker 28, Linker 29, Linker 31, Linker 32, Linker 33, Linker 34, Linker 35, Linker 36, Linker 37, Linker 38, Linker 39, Linker 40, Linker 41, Linker 42, Linker 43, Linker 44, Linker 45, Linker 46, Linker 47, Linker 48, Linker 49, and Linker 50 with the proviso that when the bifunctional linker is Linker 10, Linker 11, Linker 12, Linker 13, or Linker 14, at least one of the first or second A-chain or B-chain polypeptides is conjugated at its N-terminal amino acid to a substituent or at least the N-terminal amino acids of the first insulin heterodimer molecule are conjugated to a substituent or the N-terminal amino acids of both the first insulin heterodimer and second insulin heterodimer are conjugated to a substituent;

(b) a first B29 or B28 Lys of a first insulin heterodimer molecule having a first A-chain polypeptide and first B-chain polypeptide is conjugated to a first linker selected from the group consisting of Linker 5 and Linker 7 and a second B29 or B28 Lys of a second insulin heterodimer having a second A-chain polypeptide and second B-chain polypeptide conjugated to a second linker selected from the group consisting of Linker 4, Linker 6, Linker 8, and Linker 9 conjugated together via the first linker and the second linker;

(c) a first B29 or B28 Lys of a first insulin heterodimer molecule having a first A-chain polypeptide and first B-chain polypeptide conjugated to a first linker selected from the group consisting of Linker 5 and Linker 7 and a second B29 or B28 Lys of a second insulin heterodimer having a second A-chain polypeptide and second B-chain polypeptide conjugated to a second linker selected from the group consisting of Linker 5 and Linker 7, wherein the first and second linkers are conjugated together via a bridging linker having a structure

≡

—

R—

≡

wherein R is a covalent bond, a carbon atom, a phenyl, a heteroatom, or an optionally substituted group selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, heteroaryl, and heterocyclic;

or

(d) a first B29 or B28 Lys of a first insulin heterodimer molecule having a first A-chain polypeptide and first B-chain polypeptide conjugated to a first linker selected from the group consisting of Linker 4, Linker 6, Linker 8, and Linker 9 and a second B29 or B28 Lys of a second insulin heterodimer having a second A-chain polypeptide and second B-chain polypeptide conjugated to a second linker selected from the group consisting of Linker 4, Linker 6, Linker 8, and Linker 9, wherein the first and second linkers are conjugated together via a bridging linker having a structure

N₃—

R—

N₃

wherein R is a covalent bond, a carbon atom, a phenyl, a heteroatom, or an optionally substituted group selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, heteroaryl, and heterocyclic.

83. The insulin dimer of claim 82, wherein the substituent comprises an N-hydroxy succinimide ester linked to a group having the general formula RC(O)—

, where R can be R′

CH₂, R′

NH, R′

O, and R′

can be H, linear alkyl chain, amino acid, peptide, polyethylene glycol (PEG), saccharides.

84. The insulin dimer of claim 82, wherein the substituent is a carbamoyl group, acetyl group, glycine, methyl group, methoxy group, dimethyl group, isobutyl group, PEG1 group, AEG group, AEG-C6 alkyl group, or PEG2 group.

85-93. -93. (canceled)