ABSTRACT
INTRODUCTION: The neurokinin 3 (NK(3)) receptor is a GPCR that has been shown to modulate monoaminergic systems within regions of the brain implicated in schizophrenia. Preclinical and Phase II clinical results of osanetant and talnetant in schizophrenic patients have indicated that NK(3) antagonists may provide significant improvement of the positive symptoms and cognitive impairment associated with this disorder. Recent findings have also indicated that neurokinin B (NKB)-NK(3) signaling plays a key role in the hypothalamic regulation of reproduction in humans. AREAS COVERED: This review article discusses the latest medicinal chemistry strategies used to derive novel NK(3) receptor antagonists which have been patented during the period 2005 - 2010. EXPERT OPINION: Since the report of a beneficial effect of osanetant in schizophrenic patients, major pharmaceutical companies have been involved in this field, leading to a very large number of patent applications disclosed. Nevertheless, only three NK(3) selective antagonists entered into Phase II, but were then terminated for various reasons. Currently, the main challenge to move forward a selective NK(3) antagonist into the clinic would be to define a safety margin between the desired therapeutic effect and the effect on testosterone levels. The involvement of NKB-NK(3) signaling in reproduction in humans may also lead to new exciting indications, such as treatment for sex steroid-sensitive cancers of breast and prostate.
Subject(s)
Patents as Topic , Receptors, Neurokinin-3/antagonists & inhibitors , Amino Acid Sequence , Animals , Clinical Trials as Topic , Humans , Luteinizing Hormone/blood , Molecular Sequence Data , Neoplasms, Hormone-Dependent/drug therapy , Receptors, Neurokinin-3/chemistry , Receptors, Neurokinin-3/physiology , Reproduction , Schizophrenia/drug therapy , Testosterone/bloodABSTRACT
The rational design of a novel series of pyrrolidine derivatives as neurokinin-3 receptor antagonists is reported starting from a selective neurokinin-1 receptor antagonist. Typical representatives in this series showed in vivo efficacy after oral administration in a NK3 mediated functional assay. This series of NK3 antagonists shows promise to deliver a novel antipsychotic.
Subject(s)
Pyrrolidines/pharmacology , Receptors, Neurokinin-3/antagonists & inhibitors , Administration, Oral , Drug Design , Models, Molecular , Pyrrolidines/administration & dosage , Pyrrolidines/chemistryABSTRACT
The liver X receptors LXRalpha and LXRbeta regulate the expression of genes promoting cellular cholesterol efflux and the formation of HDL particles, and are atheroprotective. However, LXRalpha and LXRbeta also regulate the expression of genes involved in lipogenesis and hypertriglyceridemia. The identification of efficacious LXR modulators that are devoid of undesirable side effects remains a significant challenge for drug development. The X-ray structures of many LXR protein/small-molecule complexes have revealed that the ligand-binding pockets of LXRalpha and LXRbeta, despite being highly conserved, are large and flexible; these properties have allowed the design of a wide range of ligands with varied selectivity profiles. This review discusses the latest medicinal chemistry strategies used to derive novel LXR modulators with the potential for enhanced therapeutic utility and safety, and summarizes the current status of compounds that have progressed into clinical development.
Subject(s)
Liver/metabolism , Orphan Nuclear Receptors/chemistry , Orphan Nuclear Receptors/physiology , Animals , Benzoates/pharmacology , Benzylamines/pharmacology , Humans , Hydrocarbons, Fluorinated/chemistry , Hydrocarbons, Fluorinated/pharmacology , Indazoles/pharmacology , Ligands , Liver/drug effects , Liver X Receptors , Orphan Nuclear Receptors/agonists , Orphan Nuclear Receptors/antagonists & inhibitors , Protein Binding/drug effects , Protein Binding/physiology , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
A series of tetrahydro-cyclopenta[b]indoles modulating the activity of the liver-X-receptor (LXR) were derived from a high throughput screening hit. The potency and selectivity for LXRbeta versus LXRalpha was improved. One compound, administered to wild-type mice modestly increased plasma HDL-cholesterol with no change in plasma triglycerides (TG) and reduced effects on liver TG content compared to T0901317. This novel series of LXR agonists shows promise to improve therapeutic efficacy with reduced potential to increase TG.
Subject(s)
Chemistry, Pharmaceutical/methods , DNA-Binding Proteins/chemistry , Indoles/chemical synthesis , Receptors, Cytoplasmic and Nuclear/chemistry , Animals , Cholesterol, HDL/metabolism , Drug Design , Hydrocarbons, Fluorinated/pharmacology , Indoles/pharmacology , Inhibitory Concentration 50 , Liver X Receptors , Male , Mice , Mice, Inbred C57BL , Models, Chemical , Orphan Nuclear Receptors , Sulfonamides/pharmacology , Transcriptional Activation , Triglycerides/metabolismABSTRACT
A series of branched and unbranched anilinohexafluoroisopropanols related to the known sulfonamide T0901317 were prepared and evaluated as activators/modulators of both LXRalpha and LXRbeta. A structure-activity relationship was established and compounds with high potency on both the receptors were identified. Many compounds showed a tendency toward selectivity for LXRbeta versus LXRalpha. Several analogues were evaluated for effects on plasma lipoprotein levels in mice. A few of these significantly raised HDL-cholesterol levels in plasma but showed markedly different effects on liver triglyceride content, suggesting that this series may yield candidates with improved efficacy/safety profiles compared to existing molecules.
