The University of Texas System

The Administrators of the Tulane Educational Fund

Other

Anders Ljungqvist

Karl A Folkers

Cyril Y Bowers

Dong-Mei Feng

Minoru Kubota

Pui-Fun L Tang

Anna Janceka

Pui-Fun Louisa Tang

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

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.

Antagonists of LHRH

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.

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Austin, TX, United States of America

Anders Ljungqvist