The First Orally Active Low Molecular Weight Agonists for the LH Receptor: Thienopyr(im)idines with Therapeutic Potential for Ovulation Induction

Abstract

Pregnancy in pill form? The identification of low molecular weight (LMW) agonists for receptors normally triggered by high molecular weight (HMW) endogenous ligands is a great challenge for medicinal chemists. Thienopyrimidines and thienopyridines of general structures 1 and 2, respectively, are the first orally active LMW agonists for the G‐protein‐coupled luteinizing hormone receptor, which is responsible for ovulation induction. The LMW agonists display micromolar to nanomolar potencies and in vivo ovulation induction could be demonstrated in mice after oral administration. Thus, these compounds mimic the mode of action of the endogenous HMW glycopeptidic luteinizing hormone.

Rescue of expression and signaling of human luteinizing hormone G protein-coupled receptor mutants with an allosterically binding small-molecule agonist

“…In contrast to these orthosteric ligands, a group of thienopyrimidine compounds have recently been identified that allosterically activate the LH receptor (18). The present study demonstrates that one such thienopyrimidine, Org 42599 (Fig.…”

Rescue of expression and signaling of human luteinizing hormone G protein-coupled receptor mutants with an allosterically binding small-molecule agonist

“…In contrast to these orthosteric ligands, a group of thienopyrimidine compounds have recently been identified that allosterically activate the LH receptor (18). The present study demonstrates that one such thienopyrimidine, Org 42599 (Fig.…”

A Low Molecular Weight Agonist Signals by Binding to the Transmembrane Domain of Thyroid-stimulating Hormone Receptor (TSHR) and Luteinizing Hormone/Chorionic Gonadotropin Receptor (LHCGR)

“…LMW ligands of LHCGR and FSHR have the potential to become therapeutics for infertility treatment or oral contraception. It is noteworthy that in vivo efficacy of org41841 for LHCGR was demonstrated in an ovulation induction model (5) supporting the potential pharmacological utility of such synthetic ligands. Similarly, LMW antagonists of TSHR may have therapeutic potential for TSHR-mediated hyperthyroidism (24,25), while agonists might replace injected recombinant TSH in diagnostic screening for thyroid cancer (26).…”

Discovery of Selective Luteinizing Hormone Receptor Agonists Using the Bivalent Ligand Method

“…Most effective small‐molecule GpHR modulators that have been described to date are believed to exert their biological activity by binding to the seven‐helical TM region. This holds true for the highly potent low‐molecular‐weight LHR agonists, Org 41841 ( 1 )5 and Org 43553 ( 2 ),6 that are the basis of these studies. Although potent LHR agonists, neither 1 nor 2 are capable of displacing 125 I‐labeled hCG, suggesting a distinct binding site for these small‐molecule GpHR modulators.…”

Rescue of expression and signaling of human luteinizing hormone G protein-coupled receptor mutants with an allosterically binding small-molecule agonist

“…In contrast to these orthosteric ligands, a group of thienopyrimidine compounds have recently been identified that allosterically activate the LH receptor (18). The present study demonstrates that one such thienopyrimidine, Org 42599 (Fig.…”

A Low Molecular Weight Agonist Signals by Binding to the Transmembrane Domain of Thyroid-stimulating Hormone Receptor (TSHR) and Luteinizing Hormone/Chorionic Gonadotropin Receptor (LHCGR)

“…LMW ligands of LHCGR and FSHR have the potential to become therapeutics for infertility treatment or oral contraception. It is noteworthy that in vivo efficacy of org41841 for LHCGR was demonstrated in an ovulation induction model (5) supporting the potential pharmacological utility of such synthetic ligands. Similarly, LMW antagonists of TSHR may have therapeutic potential for TSHR-mediated hyperthyroidism (24,25), while agonists might replace injected recombinant TSH in diagnostic screening for thyroid cancer (26).…”

Discovery of Selective Luteinizing Hormone Receptor Agonists Using the Bivalent Ligand Method

“…Most effective small‐molecule GpHR modulators that have been described to date are believed to exert their biological activity by binding to the seven‐helical TM region. This holds true for the highly potent low‐molecular‐weight LHR agonists, Org 41841 ( 1 )5 and Org 43553 ( 2 ),6 that are the basis of these studies. Although potent LHR agonists, neither 1 nor 2 are capable of displacing 125 I‐labeled hCG, suggesting a distinct binding site for these small‐molecule GpHR modulators.…”

Rescue of expression and signaling of human luteinizing hormone G protein-coupled receptor mutants with an allosterically binding small-molecule agonist

“…In contrast to these orthosteric ligands, a group of thienopyrimidine compounds have recently been identified that allosterically activate the LH receptor (18). The present study demonstrates that one such thienopyrimidine, Org 42599 (Fig.…”

A Low Molecular Weight Agonist Signals by Binding to the Transmembrane Domain of Thyroid-stimulating Hormone Receptor (TSHR) and Luteinizing Hormone/Chorionic Gonadotropin Receptor (LHCGR)

“…LMW ligands of LHCGR and FSHR have the potential to become therapeutics for infertility treatment or oral contraception. It is noteworthy that in vivo efficacy of org41841 for LHCGR was demonstrated in an ovulation induction model (5) supporting the potential pharmacological utility of such synthetic ligands. Similarly, LMW antagonists of TSHR may have therapeutic potential for TSHR-mediated hyperthyroidism (24,25), while agonists might replace injected recombinant TSH in diagnostic screening for thyroid cancer (26).…”

Discovery of Selective Luteinizing Hormone Receptor Agonists Using the Bivalent Ligand Method

“…Most effective small‐molecule GpHR modulators that have been described to date are believed to exert their biological activity by binding to the seven‐helical TM region. This holds true for the highly potent low‐molecular‐weight LHR agonists, Org 41841 ( 1 )5 and Org 43553 ( 2 ),6 that are the basis of these studies. Although potent LHR agonists, neither 1 nor 2 are capable of displacing 125 I‐labeled hCG, suggesting a distinct binding site for these small‐molecule GpHR modulators.…”