Synthesis and characterization of an orally bioavailable small molecule agonist of the apelin receptor.

The apelin receptor (APJ) is a target for cardiovascular indications. Previously, we had identified a novel pyrazole-based agonist 1 ((S)-N-(1-(cyclobutylamino)-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-1-cyclopentyl-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carboxamide hydrochloride) of this GPCR. Systematic modification of 1 was performed to produce compounds with improved potency and ADME properties. Orally bioavailable compound 47 with favorable agonist potency (Ca2+EC50 = 24 nM, cAMPi EC50 = 6.5 nM) and pharmacokinetic properties (clearance ∼20 mL/min/kg in rats) was identified. This compound has vastly reduced brain penetration and is devoid of significant off-target liability. In summary, a potent and selective APJ agonist suitable for in vivo studies of APJ in peripheral tissues after oral administration has been identified.

Pyrazole Agonist of the Apelin Receptor Improves Symptoms of Metabolic Syndrome in Mice.

Apelin receptor agonism improves symptoms of metabolic syndrome. However, endogenous apelin peptides have short half-lives, making their utility as potential drugs limited. Previously, we had identified a novel pyrazole-based agonist scaffold. Systematic modification of this scaffold was performed to produce compounds with improved ADME properties. Compound 13 with favorable agonist potency (cAMPi EC50 = 162 nM), human liver microsome stability (T1/2 = 62 min), and pharmacokinetic profile in rodents was identified. The compound was tested in a mouse model of diet-induced obesity (DIO) and metabolic syndrome for efficacy. Treatment with 13 led to significant weight loss, hypophagia, improved glucose utilization, reduced liver steatosis, and improvement of disease-associated biomarkers. In conclusion, a small-molecule agonist of the apelin receptor has been identified that is suitable for in vivo investigation of the apelinergic system in DIO and perhaps other diseases where this receptor has been implicated to play a role.

Carbon Nanotubes Enabled Laser 3D Printing of High-Performance Titanium with Highly Concentrated Reinforcement.

Zero- to two-dimensional nanomaterials have been incorporated into metal-matrices to improve the strength of metals, but challengingly, high-volume-fraction nanomaterials are difficult to disperse uniformly in metal matrices, severely degrading the ductility of conventionally processed metals. Here, a considerably dense uniform dispersion of in situ formed nanoscale lamellar TiC reinforcement (16.1 wt %) in Ti matrix is achieved through laser-tailored 3D printing and complete reaction of Ti powder with a small amount (1.0 wt %) of carbon nanotubes (CNTs). An enhanced tensile strength of 912 MPa and an outstanding fracture elongation of 16% are simultaneously achieved for laser-printed components, showing a maximum 350% improvement in "product of strength and elongation" compared with conventional Ti. In situ nanoscale TiC reinforcement favors the formation of ultrafine equiaxed Ti grains and metallurgically coherent interface with minimal lattice misfit between TiC lamellae and Ti matrix. Our approach hopefully provides a feasible way to broaden structural applications of CNTs in load-bearing Ti-based engineering components via laser-tailored reorganization with Ti.

Influence of additive multilayer feature on thermodynamics, stress and microstructure development during laser 3D printing of aluminum-based material.

A transient three dimensional model for describing the temperature behavior, thermo-capillary convection, microstructure evolution and the resultant mechanical properties during selective laser melting of AlN/AlSi10Mg composite is proposed. The powder-solid transformation, temperature dependent physical properties and the preservation of the heat are taken into account. The effect of the additive manufacturing multilayer feature on the molten pool dynamics, cooling rate, crystal size, microstructure morphology, micro-hardness and types of the residual stress has been investigated. It shows that the operating temperature and the thermo-capillary convection obtained within the molten pool generally increases as the processing multilayers are successively added, while the thermal effect depth is negatively reduced. The preferential direction of the heat diffusion generally changes from a downward pattern, then to the slightly strengthened horizontal direction and finally to a typically horizontal one for various deposited layers being processed. Therefore, the microstructure of the solidified part along the building direction (Region I to Region V) undergoes an interesting transformation: directional columnar cellular microstructure, crosswise-extended cellular microstructure, refined cellular microstructure, fragmentation microstructure and the coarse cellular microstructure. The tensile stress and the compressive stress are comprehensively obtained within the finally solidified layers, significantly influencing the micro-hardness.

Synthesis of new compounds related to the commercial fungicide tricyclazole.

BACKGROUND: Tricyclazole is a commercial fungicide used to control rice blast. As part of re-registration activities, samples of metabolites and process impurities are required. In addition, isotopically labeled tricyclazole samples are also required. RESULTS: Four new compounds related to tricyclazole are reported. An isotopically labeled sample of tricyclazole was prepared that contained two (15)N atoms and one (13)C atom. Radiolabeled tricyclazole with (14)C at the triazole C3 position was also synthesized. A new process impurity in technical tricyclazole was identified and synthesized. A new metabolite of tricyclazole was identified, independently synthesized and characterized by X-ray crystallography. CONCLUSION: A previously unreported metabolite of tricyclazole has been identified and structurally characterized. In addition, a new process impurity has been identified by independent synthesis. Identification of these new compounds has facilitated the continued registration of this important fungicide.