Tachykinin neurokinin 3 receptor antagonists: a patent review (2005 - 2010).

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.

Rational design of novel pyrrolidine derivatives as orally active neurokinin-3 receptor antagonists.

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.

Recent progress in liver X receptor-selective modulators.

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.

Discovery of tetrahydro-cyclopenta[b]indole as selective LXRs modulator.

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.

Synthesis and evaluation of anilinohexafluoroisopropanols as activators/modulators of LXRalpha and beta.

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.