Tetrahydrocarbazole derivatives having improved biological action and improved solubility as ligands of G-protein coupled receptors (GPCR)


Pathologies associated with Luteinizing hormone-releasing hormone LHRH include a number of cancers, prostate hyperplasia, endometriosis, uterine fibroids and polycystic ovary syndrome. Analogues for LHRH have been developed to treat gynecological disorders and cancers, including leuprolide and triptorelin. However, agonists of LHRH lead to total pharmacologic castration of sex hormones, which induces side effects and does not allow for targeted adjustment.


Antagonists such as cetrorelix have been successfully introduced for controlled ovarian stimulation to treat female infertility, but are less potent than agonists. Also, current LHRH receptor ligands used are mostly decapeptides not suitable for oral administration. Therefore, potent, soluble and metabolically stable LHRH ligands that can be administered orally are needed.

This invention relates to novel tetrahydrocarbazole derivatives that have improved biological action and possess oral bioavailability as ligands for GPCRs. An example of the current technology, Compound 76 displays inhibition of LHRH receptor at low concentrations. In addition, Compound 54 effectively reduced mean plasma testosterone levels from 1.8 ng/ml to 0.4 ng/ml in male Wistar rats. This successful depletion suggests that this Compound could be useful to treat prostate cancers and other gynecological disorders.

Overview: GPCRs represent a superfamily of cell-membrane associated receptors and play a role in numerous biochemical processes, including metabolism, reproduction and development. Specifically, the peptide hormone LHRH is synthesized in the hypothalamic neurons and controls the release  of sex hormones. A number of disorders depend on stimulation by sex hormones. Treatments have been established to treat cancers and other gynecological disorders utilizing LHRH ligands.


Applications: Cancers (Prostate, breast, uterine, cervical, ovarian), fertility control and treatment, polycystic ovary syndrome

Advantages: Oral bioavailability, solubility, metabolically stable, potent

Key Words: LHRH, cancer, fertility, sex hormones, GPCRs, gynecological disorders


Inventors: Klaus Paulini, Matthias Gerlach, Eckhard Günther, Emmanuel Polymeropoulos, Silke Baasner, Peter Schmidt, Ronald Kühne, Arvid Söderhäll

Patent Status: US 7375127, US 8067456

MUSC-FRD Technology ID: P15AEZS-1 and P15AEZS-2


Patent Information:
For Information, Contact:
zzFRD Admin/Archive
MUSC Foundation for Research Development
Klaus Paulini
Matthias Gerlach
Eckhard Guenther
Emmanuel Polymeropoulos
Silke Baasner
Peter Schmidt
Ronald Kuhne
Arvid Soderhall
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