Design, synthesis, and evaluation of indolinones as inhibitors of the transforming growth factor β receptor I (TGFβRI).

Inhibition of transforming growth factor β (TGFβ) type I receptor (Alk5) offers a novel approach for the treatment of fibrotic diseases and cancer. Indolinones substituted in position 6 were identified as a new chemotype inhibiting TGFβRI concomitant with a low cross-reactivity among the human kinome. A subset of compounds showed additional inhibition of platelet-derived growth factor receptor alpha (PDGFRα), contributing to an interesting pharmacological profile.

Functional interaction of metabotropic glutamate receptor 5 and NMDA-receptor by a metabotropic glutamate receptor 5 positive allosteric modulator.

The NMDA (N-methyl-D-aspartate)-receptor is fundamentally involved in cognitive functions. Recent studies demonstrated a functional interaction between the metabotropic glutamate receptor 5 (mGlu(5) receptor) and the NMDA-receptor in neurons. In rat hippocampal slices, it was shown that activation of mGlu(5) receptor by a positive modulator in the presence of a subthreshold agonist concentration potentiated NMDA-receptor mediated currents and phosphorylation of intracellular signalling proteins.

BI 6727, a Polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity.

Purpose: Antimitotic chemotherapy remains a cornerstone of multimodality treatment for locally advanced and metastatic cancers. To identify novel mitosis-specific agents with higher selectivity than approved tubulin-binding agents (taxanes, Vinca alkaloids), we have generated inhibitors of Polo-like kinase 1, a target that functions predominantly in mitosis.

Experimental Design: The first compound in this series, suitable for i.

BI 2536, a potent and selective inhibitor of polo-like kinase 1, inhibits tumor growth in vivo.

Fine-mapping of the cell-division cycle, notably the identification of mitotic kinase signaling pathways, provides novel opportunities for cancer-drug discovery. As a key regulator of multiple steps during mitotic progression across eukaryotic species, the serine/threonine-specific Polo-like kinase 1 (Plk1) is highly expressed in malignant cells and serves as a negative prognostic marker in specific human cancer types . Here, we report the discovery of a potent small-molecule inhibitor of mammalian Plk1, BI 2536, which inhibits Plk1 enzyme activity at low nanomolar concentrations.

BI-D1870 is a specific inhibitor of the p90 RSK (ribosomal S6 kinase) isoforms in vitro and in vivo.

Hormones and growth factors induce the activation of a number of protein kinases that belong to the AGC subfamily, including isoforms of PKA, protein kinase B (also known as Akt), PKC, S6K p70 (ribosomal S6 kinase), RSK (p90 ribosomal S6 kinase) and MSK (mitogen- and stress-activated protein kinase), which then mediate many of the physiological processes that are regulated by these extracellular agonists. It can be difficult to assess the individual functions of each AGC kinase because their substrate specificities are similar. Here we describe the small molecule BI-D1870, which inhibits RSK1, RSK2, RSK3 and RSK4 in vitro with an IC(50) of 10-30 nM, but does not signi-ficantly inhibit ten other AGC kinase members and over 40 other protein kinases tested at 100-fold higher concentrations.

Synthesis and in vitro and in vivo evaluation of [11C]methyl-BIII277CL for imaging the PCP-binding site of the NMDA receptor by pet.

A new benzomorphane derivative, [11C]methyl-BIII277CL, was evaluated as a potential radiotracer for visualizing the PCP-binding site of the N-methyl-D-aspartate (NMDA) receptor by positron emission tomography (PET). Methyl-BIII277CL was prepared by reacting the desmethyl compound (BIII277CL) with dimethylsulfate. The pharmacological profile of methyl-BIII277CL was determined by in vitro receptor-screening assays.

Synthesis and structure-activity relationships of 6,7-benzomorphan derivatives as use-dependent sodium channel blockers for the treatment of stroke.

We have synthesized a series of 6,7-benzomorphan derivatives and determined their ability to bind to voltage-dependent sodium channels. We have also compared the functional consequences of this blockade in vitro and in vivo. The ability of the compounds to displace [(3)H]batrachotoxin from voltage-dependent sodium channels was compared with their ability to inhibit [(3)H]glutamate release in rat brain slices and block convulsions in the maximal electroshock test in mice.

Analgesic activity of a novel use-dependent sodium channel blocker, crobenetine, in mono-arthritic rats.

1. Although sodium channel blockers are effective analgesics in neuropathic pain, their effectiveness in inflammatory pain has been little studied. Sodium channels are substantially up-regulated in inflamed tissue, which suggests they play a role in maintenance of chronic inflammatory pain.

Potent blockade of sodium channels and protection of brain tissue from ischemia by BIII 890 CL.

We have synthesized a new benzomorphan derivative, 2R-[2alpha,3(S*), 6alpha]-1,2,3,4,5,6-hexahydro-6,11, 11-trimethyl-3-[2-(phenylmethoxy)propyl]-2, 6-methano-3-benzazocin-10-ol hydrochloride (BIII 890 CL), which displaced [(3)H]batrachotoxinin A-20alpha-benzoate from neurotoxin receptor site 2 of the Na(+) channel in rat brain synaptosomes (IC(50) = 49 nM), but exhibited only low affinity for 65 other receptors and ion channels. BIII 890 CL inhibited Na(+) channels in cells transfected with type IIA Na(+) channel alpha subunits and shifted steady-state inactivation curves to more negative potentials. The IC(50) value for the inactivated Na(+) channel was much lower (77 nM) than for Na(+) channels in the resting state (18 microM).

Effect of antipsychotic drugs and selective dopaminergic antagonists on dopamine-induced facilitatory activity in prelimbic cortical pyramidal neurons. An in vitro study.

Intracellular recordings were obtained from 119 pyramidal neurons localized in prelimbic cortex, five in the dorsal cingulate cortex, one in the infralimbic cortex, one in the border of prelimbic and cingulate cortex and two in the border of prelimbic and infralimbic cortex. The passive membrane properties of these pyramidal neurons (i.e.

N-methyl-D-aspartate receptor channel block by the enantiomeric 6,7-benzomorphans BIII 277 CL and BIII 281 CL.

BIII 277 CL ((-)-2R-[2 alpha, 3(R*),6 alpha]-3-(2-methoxypropyl)-6,11, 11-trimethyl-2,6-methano-1,2,3,4,5,6-hexahydro-3-benzazocin-9-ol hydrochloride) is a novel benzomorphan with neuroprotective and anticonvulsant properties that exhibits high affinity binding to the N-methyl-D-aspartate (NMDA) receptor but, in contrast to other structurally related benzomorphans, low affinity for mu opiate and sigma sites. Whole-cell voltage-clamp and single-channel recording were used to study the interaction of BIII 277 CL and its enantiomer BIII 281 CL with native NMDA receptors in cultured hippocampal neurons. BIII 277 CL and BIII 281 CL produced a slow use-dependent block of whole-cell NMDA receptor currents.

Synthesis and structure-activity relationships of 6,7-benzomorphan derivatives as antagonists of the NMDA receptor-channel complex.

We have synthesized a series of stereoisomeric 6,7-benzomorphan derivatives with modified N-substituents and determined their ability to antagonize the N-methyl-D-aspartate (NMDA) receptor-channel complex in vitro and in vivo. The ability of the compounds to displace [3H]-MK-801 from the channel site of the NMDA receptor in rat brain synaptosomal membranes and to inhibit NMDA-induced lethality in mice was compared with their ability to bind to the mu opioid receptor. Examination of structure-activity relationships showed that the absolute stereochemistry is critically important for differentiating these two effects.

Comparison of serodiagnostic tests and ultrasonography for cystic hydatidosis in an epidemiological study of rural Uruguay.

Cystic hydatidosis (CH) caused by Echinococcus granulosus is an important zoonosis worldwide. Several serodiagnostic and ultrasound tests are currently used for screening asymptomatic CH. The sensitivity of the serodiagnostic tests has been demonstrated by several groups to be lower than ultrasonography (US).

BIII 277 CL is a potent and specific ion-channel blocker of the NMDA receptor-channel complex.

We determined the ability of a new benzomorphan derivative [2R-[2 alpha, 3(R*),6 alpha]]-1,2,3,4,5,6-hexahydro-3-(2-methoxypropyl)- 6,11,11-trimethyl-2,6-methano-3-benzazocin-9-ol hydrochloride (BIII 277 CL) to inhibit the N-methyl-D-aspartic acid (NMDA) receptor-channel complex in vitro and in vivo. BIII 277 CL potently displaced [3H]MK-801 binding from the NMDA receptor-channel complex in synaptosomal membrane preparations from rat brain cortex (Ki = 4.49 nmol/l).

Trypanosoma cruzi infection enhances polyreactive antibody response in an acute case of human Chagas' disease.

The kinetics of antibody response in an acute case of human Chagas' disease was investigated. Hypergammaglubulinaemia appeared at day 17 of infection, and persisted after 66 days of infection, at which time parasitaemia became undetectable. Titration of immunoglobulins showed that the three principal isotypes were involved in the response, emphasizing polyclonal B cell activation.