Diaminopyrimidines, diaminopyridines and diaminopyridazines as histamine H4 receptor modulators.

Previously disclosed H4 receptor modulators, the triamino substituted pyridines and pyrimidines, contain a free primary amino (-NH2) group. In this Letter we demonstrate that an exocyclic amine (NH2) is not needed to maintain affinity, and also show a significant divergence in the SAR of the pendant diamine component. These des-NH2 azacycles also show a distinct functional spectrum, that appears to be influenced by the diamine component; in the case of the 1,3-amino pyrimidines, the preferred diamine is the amino pyrrolidine instead of the more common piperazines. Finally, we introduce 3,5-diamino pyridazines as novel histamine H4 antagonists.

Effects of strip cropping with reducing row spacing and super absorbent polymer on yield and water productivity of oat (Avena sativa L.) under drip irrigation in Inner Mongolia, China.

With the serious shortage of water resources and the development of water-saving agriculture, the application of drip irrigation has been paid more and more attention. But there was lack of oat planting methods suitable for drip irrigation, currently. In order to establish an efficient oat planting method for drip irrigation, a study was conducted at Agriculture and Forestry Sciences of Ulanqab, Inner Mongolia during the season (2019-2020) to evaluate the effect of strip cropping with reducing row spacing and super absorbent polymer on the yield and water use efficiency of oat. To conduct the field trials, a split plot system in three replications was established. Three planting patterns were in the main plots, including conventional cropping with 20 cm equal row spacing (PA), strip cropping with the 15 cm row spacing (PB) and strip cropping with the 10 cm row spacing (PC), and two super absorbent polymer levels were in the subplots, including 22.5 kg ha-2 (Y) and 0 (N). The results showed that, compared with PA, PB and PC both decreased the irrigation volumes by 4.5-18.4 mm, and the irrigation volumes of PB was lower than that of PC. When super absorbent polymers were applied, compared with PA, PB significantly increased grain yield and above-ground biomass, but PC had the opposite effects. The grain yield and above-ground biomass of PB significantly increased by 16.65% and 7.31% on average in two years, respectively. And the increasing of grain yield was attributed by the significant increasing of pike number and kernel number per spike. But when super absorbent polymers were not applied, PB had no significant effects on grain yield and above-ground biomass. PB also had the significant effects on regulating water use of oats weather or not super absorbent polymers were applied, it significantly increased the precipitation ratio by 2.64% (PBY) and 2.13% (PBN) and decreased irrigation ration by 3.32% (PBY) and 5.28% (PBN) on average in two years. Although PB and PC both decreased the total evapotranspiration, but PB increased WUE and PC deceased WUE. The WUE of PB increased by 19.70% (PBY) and 9.87% (PBN) on average in two years. Also PB had the highest economic benefits in all treatments. In conclusion, a drip irrigation oat planting pattern was proposed, which the row spacing is 15 cm, adjusted the equal row spacing planting to 8-row strip planting, with a belt spacing of 30 cm, combined with the application of 22.5 kg ha-2 applying super absorbent polymers. And this oat planting pattern is a viable strategy to improve oat productivity.

[Effects of moisture and humic acid on the metabolism of oat fructans]. / æ°´åˆ†å’Œè æ¤é ¸å¯¹ç‡•éº¦æžœèšç³–ä»£è°¢çš„å½±å“.

To provide theoretical guidance and technical support for oat production in dry farming area, we exa-mined the effects of moisture and humic acid (HA) on the accumulation and distribution of non-structural carbohydrates (NSC) in different organs of oat, as well as the mechanism of sugar metabolism and grain weight formation of oat. Two oat cultivars, 'Mengnong Dayan 1' and 'Neiyan 5', were used as experimental material. HA and clean water (CK) were foliar sprayed under dry framing (without irrigation) and limited irrigation (irrigated twice at jointing and heading stage). The dynamics of NSC components in stems, leaves and panicles, as well as the changes of carbon metabolism-related enzyme activities at different growth stages of oats after flowering were measured. Results showed that the trend of the contents of NSC in stems, leaves and panicles, in both two oat cultivars increased firstly and then decreased with the prolong of post-anthesis time. The contents of NSC in different organs were similar between two oat cultivars. Under irrigation treatment, the fructan content in panicle for Mengnong Dayan 1 of HA was higher than that of CK, with magnitude of enhancement being significantly greater than that corresponding treatment under dry farming. Under irrigation condition, the fructan, invertase activities in leaves and grain weight per panicle for Mengnong Dayan 1 of HA were increased by 27.1%, 30.6% and 55.9% compared with CK, respectively. Further, the increase trend under irrigation was stronger than that under dry farming condition. For Mengnong Dayan 1, the 1000-grain weight and grain weight per panicle were positively correlated with the content of fructan in leaves. In conclusion, the synergistic effect of moisture and humic acid could effectively regulate the accumulation of oat fructans and the activities of carbon metabolic enzymes, consequently promoting the formation of yield.

Indazole-based ligands for estrogen-related receptor α as potential anti-diabetic agents.

Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of indazole-based N-alkylthiazolidenediones, which function in biochemical assays as selective inverse agonists against this receptor. Series optimization provided several potent analogues that inhibited the recruitment of a co-activator peptide fragment in vitro (IC50s < 50 nM) and reduced fasted circulating insulin and triglyceride levels in a sub-chronic pre-diabetic rat model when administered orally (10 mg/kg). A multi-parametric optimization strategy led to the identification of 50 as an advanced lead, which was more extensively evaluated in additional diabetic models. Chronic oral administration of 50 in two murine models of obesity and insulin resistance improved glucose control and reduced circulating triglycerides with efficacies similar to that of rosiglitazone. Importantly, these effects were attained without the concomitant weight gain that is typically observed with the latter agent. Thus, these studies provide additional support for the development of such molecules for the potential treatment of metabolic diseases.

On the mechanism of the directed ortho and remote metalation reactions of N,N-dialkylbiphenyl 2-carboxamides.

A study concerning the mechanism of the LDA-mediated ortho and remote metalation of N,N-dialkyl-2-biphenyl carboxamides (e.g., 4a) is reported. On the basis of site-selective lithiation/electrophile quench experiments, including deuteration, the LDA metalation of 4 is proposed to involve initial amide-base complexation (CIPE) and equilibrium formation of 5, whose fast reaction with an in situ electrophile (TMSCl) to afford 6 prevents its equilibration with 7. In the absence of an electrophile, 5 undergoes equilibration via 4a with 7, whose fate is instantaneous cyclization to a stable tetrahedral carbinolamine oxide 8 which, only upon hydrolysis, affords fluorenone (3).

Characterization of alternatively spliced and truncated forms of the Arf guanine nucleotide exchange factor GBF1 defines regions important for activity.

Analysis of multiple transcripts for the Arf-specific guanine nucleotide exchange factor GBF1 identified three positions displaying small in-frame deletions and insertions. Sequencing of genomic DNA for CHO GBF1 and analysis of the human gene established that those variations were consistent with alternate splicing events. RT-PCR analysis of CHO mRNA confirmed that these small in-frame deletions occurred at significant and similar frequencies in both WT and BFA resistant CHO cells. These splice variants behaved like GBF1 in biological assays based on the observation that GBF1 is cytotoxic at high levels but will confer resistance to BFA when moderately overexpressed. Comparison of variants with larger deletions defined regions of 75 (exons 5-7) and 412 (exons 31-39) amino acid residues that were required for cell killing but were dispensable for promoting BFA resistance.

Discovery and SAR of novel Naphthyridines as potent inhibitors of spleen tyrosine kinase (SYK).

The discovery of novel 5,7-disubstituted[1,6]naphthyridines as potent inhibitors of Spleen Tyrosine Kinase (SYK) is discussed. The SAR reveals the necessity for a 7-aryl group with preference towards para substitution and that this in combination with 5-aminoalkylamino substituents further improved the potency of the compounds. The initial SAR as well as a survey of the other positions is discussed in detail.