Fused thiazolyl alkynes as potent mGlu5 receptor positive allosteric modulators

A new series of potent fused thiazole mGlu₅ receptor positive allosteric modulators (PAMs) (10, 11 and 27–31) are disclosed and details of the SAR and optimization are described. Optimization of alkynyl thiazole 9 (Lu AF11205) led to the identification of potent fused thiazole analogs 10b, 27a, 28j and 31d. In general, substituted cycloalkyl, aryl and heteroaryl carboxamides, and carbamate analogs are mGlu₅ PAMs, whereas smaller alkyl carboxamide, sulfonamide and sulfamide analogs tend to be mGlu₅ negative allosteric modulators (NAMs).     

Aminoimidazoles as bioisosteres of acylguanidines: novel, potent, selective and orally bioavailable inhibitors of the sodium hydrogen exchanger isoform-1

Inhibition of the sodium hydrogen exchanger isoform-1 (NHE-1) has been shown to limit damage to the myocardium under ischemic conditions in animals. While most known NHE-1 inhibitors are acylguanidines, this report describes the design and synthesis of a series of heterocyclic inhibitors of NHE-1 including aminoimidazoles with undiminished in vitro activity and oral bioavailability.     

Galactose-substituted alginate: preliminary characterization and study of gelling properties

Coupling of alginate with 1-amino-1-deoxygalactose in the presence of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide results in a substituted polymer containing galactose side linked via an amide bond. To clarify the degree and pattern of substitution, a (1)H NMR study on the anomeric region of modified alginate, polymannuronate, alginate enriched in guluronic acid (G-enriched alginate), and polyalternating MG, was carried out (G, alpha-l-guluronic acid; M, beta-d-mannuronic acid). From the resonance of the proton at position 1 of galactosylamine, it was possible to determine the amount of galactose linked to mannuronic and to guluronic residues, respectively. Furthermore, (1)H NMR spectroscopy revealed a higher reactivity of guluronic residues for low degrees of conversion. Modified alginates with 7% and 19% of substitution are both able to form stable beads in the presence of calcium ions. The effect of galactose substitution on the dimensions, swelling, and stability of the beads has been studied and the cytotoxicity of the modified polymer evaluated in preliminary biological tests.     

Mycelial colonization by bradyrhizobia and azorhizobia

This study examines mycelial colonization of common soil fungi by bradyrhizobia and an azorhizobial strain, resulting in the forming of biofilms. The effects of the fungal exudates on a bradyrhizobial strain have also been investigated. Bradyrhizobia gradually colonized the mycelia for about 18 days, after which the biofilm structures collapsed with the release of the rhizobial cell clusters to the culture medium. The azorhizobial strain showed differential colonization of the mycelia. In general, there were no considerable mycotoxin effects of the fungal exudates on the bradyrhizobial strain used, instead the rhizobial strain utilized the exudates as a source of nutrition. This study indicates that the present microbial association with biofilm formation has important implications in the survival of rhizobia under adverse soil conditions devoid of vegetation. Further, it could have developed an as yet unidentified nitrogen fixing system that could have contributed to the nitrogen economy of soils.     

Arrest of chlorophyll accumulation prior to anthocyanin formation in Euphorbia pulcherrima

Euphorbia pulcherrima Klotz plants exposed to short days (11 h light/13 h dark) for a period of eight weeks, developed flowers and a red canopy consisting of bracts and few true leaves. Plants maintained for three weeks under short day conditions, failed to produce flower primordia or a red canopy in the following 5 weeks in continuous light. Between the 4th and 5th short day week, the youngest leaves began to accumulate anthocyanin and turned red while the apical meristems differentiated into flower primordia. Chlorophyll accumulation ceased at the onset of anthocyanin synthesis and the protein content per unit leaf area declined. mRNA for glutamyl-tRNA^Glu synthetase (EC 6.1.1.17) and glutamyl-tRNA^Glu reductase also declined during this period. Western blot analysis revealed a loss of glutamyl-tRNA^Glu reductase, glutamate 1-semialdehyde (EC 5.4.3.8) and the Mg-chelatase subunits, Olive and CH42, in the last 2 to 4 weeks of the photoperiod.     

Discovery of Lu AA33810: a highly selective and potent NPY5 antagonist with in vivo efficacy in a model of mood disorder

The structure-activity relationship of a series of tricyclic-sulfonamide compounds 11-32 culminating in the discovery of N-[trans-4-(4,5-dihydro-3,6-dithia-1-aza-benzo[e]azulen-2-ylamino)-cyclohexylmethyl]-methanesulfonamide (15, Lu AA33810) is reported. Compound 15 was identified as a selective and high affinity NPY5 antagonist with good oral bioavailability in mice (42%) and rats (92%). Dose dependent inhibition of feeding was observed after i.c.v. injection of the selective NPY5 agonist ([cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPP). In addition, ip administration of Lu AA33810 (10 mg/kg) produced antidepressant-like effects in a rat model of chronic mild stress.     

Cyanobacterial glutamate 1-semialdehyde aminotransferase: requirement for pyridoxamine phosphate

Glutamate 1-semialdehyde aminotransferase has been separated from metabolically related activities by gel filtration and affinity chromatography. The enzyme was inhibited by gabaculin, 4-amino 5-fluoropentanoic acid and pyridoxal 5-phosphate and stimulated by pyridoxamine 5-phosphate. The activity of enzyme recovered by elution after electrophoresis in non-denaturing polyacrylamide gels was wholly dependent on pyridoxamine 5-phosphate. A mechanism for the enzyme-catalysed reaction based on these observations is discussed.Abbreviations AFPA 4-amino 5-fluoropentanoic acid - ALA -aminolaevulinic acid - DTT dithiothreitol - GSA glutamate 1-semialdehyde - PAL-P pyridoxal 5-phosphate - PAM-P pyridoxamine 5-phosphate - PCC Paris Culture Collection     

Indolyl and dihydroindolyl N-glycinamides as potent and in vivo active NPY5 antagonists

A novel series of indolyl and dihydroindolyl glycinamides were identified as potent NPY5 antagonists with in vivo activity from screen hit 1. The dihydroindolyl glycinamide 10a significantly inhibits NPY5 agonist induced feeding at a dose of 0.1 mg/kg. The indolyl glycinamide 12c also inhibits NPY5 agonist induced feeding at a dose of 1 mg/kg. Both compounds 10a and 12c represent potential tools for further investigation into the biology of the NPY5 receptor.