# US 8,772,229 B2 · Methods for synthesis and uses of inhibitors of ghrelin O-acyltransferase as potential therapeutic agents for obesity and diabetes > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,772,229 B2 - Document ID: US8772229B2 - Status: Granted - Kind: B2 - Application number: 13/122,438 - Filed: 2009-09-18 - Published: 2011-10-20 - Granted: 2014-07-08 - Earliest claimed: 2008-10-03 - Assignees: The Johns Hopkins University - Applicants: Philip A. Cole; Bradley P. Barnett; Yousang Hwang; Jef D. Boeke - Inventors: Philip A. Cole; Bradley P. Barnett; Yousang Hwang; Jef D. Boeke - Web page: https://patentgrep.com/patent/US8772229B2 ## CPC - C07K 14/60: Growth hormone-releasing factor [GH-RF], i.e. somatoliberin - A61K 47/645: {Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT} - A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system - A61P 3/04: Anorexiants; Antiobesity agents - A61P 3/10: for hyperglycaemia, e.g. antidiabetics - A61P 7/12: Antidiuretics, e.g. drugs for diabetes insipidus (ADH A61P5/10) - 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) - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The invention provides inhibitors of ghrelin O-acyltransferase, and methods of making and using them. In some embodiments, the invention provides bisubstrate analog inhibitors of ghrelin O-acyltransferase, which can be effective in treating, for example, obesity and diabetes mellitus. ## Claims ### Claim 1 A compound of the formula (I): wherein R is absent, or is an organic moiety selected from the group consisting of a substituted or unsubstituted alkyl group, and a substituted or unsubstituted peptide chain and wherein TAT is the peptide shown in SEQ ID NO:3. ### Claim 2 (depends on 1) The compound of claim 1, wherein R is a peptide of 12 amino acid residues so that the peptide GS to TAT is represented by SEQ ID NO:21. ### Claim 3 (depends on 1) The compound of claim 1, wherein R is a peptide of 7 amino acid residues corresponding to ghrelin residues 4 through 10 so that the peptide GS to TAT is represented by SEQ ID NO:22. ### Claim 4 (depends on 1) The compound of claim 1, wherein R is a peptide of 12 amino acid residues corresponding to ghrelin residues 4 through 15 so that the peptide GS to TAT is represented by SEQ ID NO:23. ### Claim 5 (depends on 1) A composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient or carrier. ### Claim 6 (depends on 1) A method for preparing the compound of one of claim 1, comprising the steps of: providing a ghrelin peptide sequence comprising from 3 to 15 N-terminal amino acid residues, wherein the serine residue at the 3 position is replaced with alloc-protected 1,2-diaminopropionic acid and wherein D4-Tat (“D4” disclosed as SEQ ID No:26) is bound to one end of the peptide sequence (SEQ ID NO: 26); combining the ghrelin peptide sequence with Pd(PPh3)4 palladium reagent, n-bromo octanoic anhydride and Reagent K in one or more reaction vessels to obtain a bromo-octanoylated intermediate; and combining the bromo-octanoylated intermediate with coenzyme A. ### Claim 7 (depends on 3) A method for treating obesity comprising administering to a subject a composition comprising a therapeutically effective amount of the composition of claim 3, wherein Xaa at position 11 of SEQ ID NO:22 is Ahx. ### Claim 8 (depends on 7) The method of claim 7, wherein administering the composition brings about a greater loss of fat mass than lean mass in the subject. ### Claim 9 (depends on 7) The method of claim 7, wherein administering the composition brings about an increase in the ratio of ghrelin to acyl-ghrelin in the subject. ### Claim 10 (depends on 7) The method of claim 7, wherein the therapeutically effective amount is at least about 5 mg/kg subject body weight. ### Claim 11 (depends on 7) The method of claim 7, wherein the therapeutically effective amount is at least about 25 mg/kg subject body weight. ### Claim 12 (depends on 3) A method for treating Type II diabetes comprising administering to a subject a composition comprising a therapeutically effective amount of the composition of claim 3, wherein Xaa at position 11 of SEQ ID NO:22 is Ahx. ### Claim 13 (depends on 12) The method of claim 12, wherein administering the composition brings about an increased production of insulin in the subject. ### Claim 14 (depends on 12) The method of claim 12, wherein administering the composition brings about a reduction in uncoupling-protein 2 (UCP-2) mRNA levels in the subject. ### Claim 15 (depends on 12) The method of claim 12, wherein the therapeutically effective amount is at least about 5 mg/kg subject body weight. ### Claim 16 (depends on 12) The method of claim 12, wherein the therapeutically effective amount is at least about 25 mg/kg subject body weight. ### Claim 17 (depends on 1) A kit comprising a composition comprising at least one dose of a therapeutically effective amount of the compound of claim 1.