The Administrators of the Tulane Educational Fund

University of Texas System

Mcgill University

Eastman-kodak Company

Polygen Holding Corporation

Other

Beckman Instruments, Inc.

Cyril Y Bowers

Karl A Folkers

David H Coy

Charles H Foster

John C Hubbs

Dong-Mei Feng

Wayne Livingston Cody

Frank A Momany

Gloria S Tannenbaum

Minoru Kubota

Anders Ljungqvist

Simon J Hocart

Pui-Fun L Tang

Ching H Chang

Xu Jie-cheng

Yongwu Liang

Frank Momany

Teresa M Kubiak

Anna Janceka

Anna Janecka

Pui-Fun Louisa Tang

Janusz Stepinski

The invention provides methods for treatment, prevention or management of obesity, obesity related disorders, diabetes mellitus, and metabolic syndrome in a subject by administering a ghrelin O-acyltransferase (GOAT) inhibitor and/or a ghrelin receptor antagonist to the subject. The invention also provides ghrelin receptor antagonists of formula (VII): A-A-A-Gly-Ser-A-Phe-Leu-A-A-A-A, wherein each of A, A, and Ais independently absent, an amino acid, or an amino protecting group; each of A, A, A, and Ais independently absent or an amino acid; and Ais a serine conjugated with a &#x2014;C(O)C-Calky or a diaminopropionic acid conjugated with a &#x2014;C(O)C-Calkyl group, provided that at least one of A, A, or Ais present.

Methods of inhibiting the ghrelin/growth hormone secretatogue receptor pathway and uses thereof

The present invention provides novel peptides that can modulate the ghrelin receptor (growth hormone secretagogue receptor, GHS-R1a and sub-types, isoforms and variants thereof). These peptides are useful as antagonists of the ghrelin receptor as well as inverse agonist, partial agonist or a combination of these activities as medicaments for treatment and prevention of a range of medical conditions including, but not limited to, metabolic and/or endocrine disorders, gastrointestinal disorders, cardiovascular disorders, obesity and obesity-associated disorders, diabetes, central nervous system disorders, genetic disorders, and hyperpro-liferative disorders.

Growth hormone secretatogue receptor antagonists and uses thereof

The invention provides methods for treatment, prevention or management of obesity, obesity related disorders, diabetes mellitus, and metabolic syndrome in a subject by administering a ghrelin O-acyltransferase (GOAT) inhibitor and/or a ghrelin receptor antagonist to the subject. The invention also provides ghrelin receptor antagonists of formula (VII): A-A-A-Gly-Ser-A-Phe-Leu-A-A-A-A(SEQ ID NO: 93), wherein each of A, A, and Ais independently absent, an amino acid, or an amino protecting group; each of A, A, A, and Ais independently absent or an amino acid; and Ais a serine conjugated with a &#x2014;(O)C-Calky or a diaminopropionic acid conjugated with a &#x2014;C(O)C-Calkyl group, provided that at least one of A, A, or Ais present.

The present invention provides novel compounds that have been demonstrated to be modulators of the ghrelin receptor (growth hormone secretagogue receptor, GHS-R1a and subtypes, iso forms and variants thereof). These compounds are useful as antagonists of the ghrelin receptor as well as inverse agonist, partial agonist or a combination of these activities as medicaments for treatment and prevention of a range of medical conditions including, but not limited to, metabolic and/or endocrine disorders, gastrointestinal disorders, cardiovascular disorders, obesity and obesity-associated disorders, diabetes, central nervous system disorders, genetic disorders, and hyperproliferative disorders.

Ghrelin/growth hormone releasing peptide/growth hormone secretatogue receptor antagonists and uses thereof

Compounds that promote growth hormone releasing activity are disclosed. These compounds have the formula:A-A-X; A-X'; or A-Y These compounds can be present in a pharmaceutical composition. The compounds can be used with a second compound that acts as an agonist at the growth hormone releasing hormone receptor or which inhibits the effects of somatostatin. These compounds can be used for a variety of uses such as treating hypothalamic pituitary dwarfism, osteoporosis, burns, or promoting wound healing.

Compounds having growth hormone releasing activity

Novel peptides of the formula A.sub.1 -A.sub.2 -C.sub.1 -C.sub.2 -C.sub.3 -A.sub.5 are disclosed which promote the release of growth hormone when administered to animals. These peptides can be used therapeutically.

Polypeptide analogues having growth hormone releasing activity

Antide is the decapeptide, N-Ac-D-2-Nal,D-pClPhe, D-3-Pal, Ser,NicLys, D-NicLys, Leu, ILys, Pro, D-Ala,NH.sub.2 which is an antagonist of luteinizing hormone releasing hormone (LHRH). This decapeptide, like others of the present invention, has high antiovulatory activity (AOA) and releases negligible histamine. Antide is scheduled for scale-up, safety testing and evaluation in the experimental primate and in clinical medicine. Numerous other peptides having structures related to Antide were prepared and tested. These peptides had variations primarily in positions 5, 6, 7, and 8. Of these, N-Ac-D-2-Nal, D-pClPhe,D-3-Pal,Ser,PicLys,cis-DPzACAla,Leu,ILys,Pro,D-Ala-NH.sub.2 was one of the most potent and had higher antiovulatory activity than Antide, i.e. 73%/0.25 ug and 100%/0.5 ug vs. 36%/0.5 ug and 100%/1.0 ug. Antide showed significant, (p&lt;0.001) duration of action, when injected at a dose of 10 ug, 44 hours before 50 ng of the agonist, �D-3-Qal.sup.6 !-LHRH. Antide showed oral AOA at 600 ug (73%) and at 1200 ug (100%) with negligible difference being found between water and corn oil oral formulations. In the antagonists prepared according to the present invention, arginine and its derivatives were not utilized. Lysine was converted into derivatives with acyl groups or with alkyl groups on the E-amino group. The amino acid ornithine was acylated or alkylated on the d-amino group. Both the L- and D- forms of lysine and the L-form of ornithine were used in synthesizing these acyl and alkyl derivatives. Structurally related intermediates were also synthesized. All together, many new peptides were synthesized by the basic and minimal concepts of ten variables for anti-ovulation activity and ten variables for histamine release, which may be independent or partially overlapping. On such a basis, the number of such peptides that can be designed becomes overwhelming, and every reasonable priority must be considered to reduce the number of peptides to be synthesized in the hope that a discovery will be realized.

Methods for using LHRH antagonists with low histamine release

Novel peptides of the formula A.sub.1 -A.sub.2 -Ala-Trp-DPhe-A.sub.5 are disclosed which promote the release of growth hormone when administered to animals. These peptides can be used therapeutically.

LHRH analogs and congeners with high water solubility have been synthesized. These new analogs had 0%-100% antiovulatory activity at a 0.5 .mu.g dosage and 0%-80% at 0.25 .mu.g. The ED.sub.50 for histamine release was 30.5 .mu.g/ml-&gt;300 .mu.g/ml.

Antagonists of LHRH

Disclosed are novel polypeptide compounds which promote the release and elevation of growth hormone levels in the blood of animals. Also disclosed are methods of promoting the release and elevation of growth hormone levels in the blood of animals using the disclosed polypeptide compounds.

Polypeptide compounds having growth hormone releasing activity

Novel polypeptides which promote the release of growth hormone when administered to animals are described. These polypeptides have the formula:

LHRH antagonists similar to antide and congeners with higher water solubility have been synthesized by substitutions in positions 1, 5 or 6 with hydrophilic residues. These peptides have antiovulatory activity with minimal histamine releasing effect.

Antide is the decapeptide, N--Ac--D--2--Nal,D--pClPhe, D--3--Pal, Ser,NicLys, D--NicLys, Leu, ILys, Pro, D--Ala,NH.sub.2 which is an antagonist of luteinizing hormone releasing hormone (LHRH). This decapeptide, like others of the present invention, has high antiovulatory activity (AOA) and releases negligible histamine. Antide is scheduled for scale-up, safety testing and evaluation in the experimental primate and in clinical medicine. Numerous other peptides having structures related to Antide were prepared and tested. These peptides had variations primarily in positions 5, 6, 7, and 8. Of these, N--Ac--D--2--Nal, D--pClPhe,D--3--Pal,Ser,PicLys,cis--DpzACAla, Leu,ILys,pro,D--Ala--NH.sub.2 was one of the most potent and had higher antiovulatory activity than Antide, i.e. 73%/0.25 ug and 100%/0.5 ug vs. 36%/0.5 ug and 100%/1.0 ug. Antide showed significant, (p&lt;0.001) duration of action, when injected at a dose of 10 ug, 44 hours before 50 ng of the agonist, [D--3--Qal.sup.6 ]--LHRH. Antide showed oral AOA at 600 ug (73%) and at 1200 ug (100%) with negligible difference being found between water and corn oil oral formulations.

CHRH antagonists with low histamine release

The objective of the research was the achievement of antagonists of the luteinizing hormone releasing hormone (LHRH) which would have adequate antagonistic activity to prevent ovulation, and yet would not have a pronounced structural feature to release a histamine, in vivo. Some existing antagonists of LHRH produced edema of the face and extremities in rats. This recent recognition of the edematogenic and anaphylactoid activities of an antagonist of LHRH necessitated new structural changes if such antagonists were to be considered for potential use as contraceptive agents in the human. Consequently, 57 peptides have been designed, synthesized and bioassayed toward achieving a potent antagonist which releases negligible histamine. Since there was no predictable structural sequence which offered assurance of such achievement, it was necessary to design, synthesize and bioassay a very large number of peptides having diverse structural changes toward ultimately discovering an antagonist with the necessary potency of antiovulatory activity and the necessary negligible release of histamine. Ultimately, this objective was achieved, and this application describes the diverse and unpredictable many positive steps which finally led to the objectives.

Growing community of inventors

New Orleans, LA, United States of America

Cyril Y Bowers