Selective estrogen receptor degraders with novel structural motifs induce regression in a tamoxifen-resistant breast cancer xenograft

Potent estrogen receptor ligands typically contain a phenolic hydrogen-bond donor. The indazole of the selective estrogen receptor degrader (SERD) ARN-810 is believed to mimic this. Disclosed herein is the discovery of ARN-810 analogs which lack this hydrogen-bond donor. These SERDs induced tumor regression in a tamoxifen-resistant breast cancer xenograft, demonstrating that the indazole NH is not necessary for robust ER-modulation and anti-tumor activity.     

Identification and characterization of amino-piperidinequinolones and quinazolinones as MCHr1 antagonists

Several potent, functionally active MCHr1 antagonists derived from quinolin-2(1H)-ones and quinazoline-2(1H)-ones have been synthesized and evaluated. Pyridylmethyl substitution at the quinolone 1-position results in derivatives with low-nM binding potency and good selectivity with respect to hERG binding.     

Rho GTPases, dendritic structure, and mental retardation

A consistent feature of neurons in patients with mental retardation is abnormal dendritic structure and/or alterations in dendritic spine morphology. Deficits in the regulation of the dendritic cytoskeleton affect both the structure and function of dendrites and synapses and are believed to underlie mental retardation in some instances. In support of this, there is good evidence that alterations in signaling pathways involving the Rho family of small GTPases, key regulators of the actin and microtubule cytoskeletons, contribute to both syndromic and nonsyndromic mental retardation disorders. Because the Rho GTPases have been shown to play increasingly well-defined roles in determining dendrite and dendritic spine development and morphology, Rho signaling has been suggested to be important for normal cognition. The purpose of this review is to summarize recent data on the Rho GTPases pertaining to dendrite and dendritic spine morphogenesis, as well as to highlight their involvement in mental retardation resulting from a variety of genetic mutations within regulators and effectors of these molecules.     

Benzazoles as allosteric potentiators of metabotropic glutamate receptor 2 (mGluR2): efficacy in an animal model for schizophrenia

Metabotropic glutamate receptor 2 (mGluR2) has been implicated in a variety of CNS disorders, including schizophrenia. Disclosed herein is the development of a new series of allosteric potentiators of mGluR2. Structure-activity relationship studies in conjunction with pharmacokinetic data led to the discovery of indole 5, which is active in an animal model for schizophrenia.     

Identification of aminopiperidine benzamides as MCHr1 antagonists

The identification of a novel series of benzamide-containing MCHr1 antagonists is described. Compound 22 displayed moderate efficacy in a diet induced obesity mice model.     

Water-soluble PDE4 inhibitors for the treatment of dry eye

PDE4 inhibitors have the potential to alleviate the symptoms and underlying inflammation associated with dry eye. Disclosed herein is the development of a novel series of water-soluble PDE4 inhibitors. Our studies led to the discovery of coumarin 18, which is effective in a rabbit model of dry eye and a tear secretion test in rats.     

The role of Rho GTPase proteins in CNS neuronal migration

The architectonics of the mammalian brain arise from a remarkable range of directed cell migrations, which orchestrate the emergence of cortical neuronal layers and pattern brain circuitry. At different stages of cortical histogenesis, specific modes of cell motility are essential to the stepwise formation of cortical architecture. These movements range from interkinetic nuclear movements in the ventricular zone, to migrations of early-born, postmitotic polymorphic cells into the preplate, to the radial migration of precursors of cortical output neurons across the thickening cortical wall, and the vast, tangential migrations of interneurons from the basal forebrain into the emerging cortical layers. In all cases, actomyosin motors act in concert with cell adhesion receptor systems to provide the force and traction needed for forward movement. As key regulators of actin and microtubule cytoskeletons, cell polarity, and adhesion, the Rho GTPases play critical roles in CNS neuronal migration. This review will focus on the different types of migration in the developing neocortex and cerebellar cortex, and the role of the Rho GTPases, their regulators and effectors in these CNS migrations, with particular emphasis on their involvement in radial migration.     

Dipyridyl amines: potent metabotropic glutamate subtype 5 receptor antagonists

Modulation of the metabotropic glutamate subtype 5 (mGlu5) receptor may be useful in the treatment of a variety of central nervous system disorders. Herein, we report on the discovery, synthesis, and biological evaluation of dipyridyl amines as small molecule mGlu5 antagonists.