Synthesis of 7-(tetrahydropyran-2-yl)- and 7-(4-acetoxytetrahydropyran-2-yl)-ε-rhodomycinone and 7-(tetrahydropyran-2-yl)-ε-pyrromycinone

The ¹³C.n.m.r spectra of water-soluble and -insoluble glucans synthesized by enzymes isolated from six strains of Streptococcus mutans are interpreted. The glucans are shown to be composed primarily of α(1→3)- and α-(1→6)-linked glucosyl residues, and the relative abundance of each linkage is estimated from peak areas. Treatment of water-insoluble glucans with dextranase is found to result in water-soluble and -insoluble products, the former enriched in α-(1→6)-linkages and the latter in α-(1→3)-linkages. The structural conclusions arrived at by ¹³C-n.m.r. spectroscopy are consistent with data from methylation analysis and ¹H-n.m.r. spectroscopy.     

3-[(Imidazolidin-2-yl)imino]indazole ligands with selectivity for the α(2)-adrenoceptor compared to the imidazoline I(1) receptor

A series of 3-[(4,5-dihydroimidazolidin-2-yl)imino]indazoles has been synthesized as positional analogues of marsanidine, a highly selective ??₂-adrenoceptor ligand. Parent compound 4a and its 4-chloro (4c) and 4-methyl (4d) derivatives display ??₂-adrenoceptor affinity at nanomolar concentrations (K_i = 39.4, 15.9 and 22.6 nM, respectively) and relatively high ??₂/I₁ selectivity ratios of 82, 115 and 690, respectively. Evidence was obtained that these compounds act as partial agonists at ??_2A-adrenoceptors. Compound 4d with intrinsic activity comparable with that of marsanidine, but lower than that of clonidine, elicited pronounced cardiovascular effects in anesthetized rats at doses as low as 0.01 mg/kg iv     

Discovery of novel N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides as potent RORγt inhibitors

Novel series of N-(5-(arylcarbonyl)thiazol-2-yl)amides and N-(5-(arylcarbonyl)thiophen-2-yl)amides were discovered as potent retinoic acid receptor-related orphan receptor-gamma-t (RORγt) inhibitors. SAR studies of the RORγt HTS hit 6a led to identification of thiazole ketone amide 8h and thiophene ketone amide 9g with high binding affinity and inhibitory activity of Th17 cell differentiation. Compound 8h showed in vivo efficacy in both mouse experimental autoimmune encephalomyelitis (EAE) and collagen induced arthritis (CIA) models via oral administration.     

Binuclear copper(II) complexes of tetradentate (Ne) diazine ligands. Crystal structures of [μ-1,4-Bis(4,6-dimethyl-2-pyridylamino)phthalazine-N,μ-N3,μN3,N]-(μ-Dichloro)dichlorodicopper(II), [μ-3,6-Bis(2-pyridylthio)pyridazine-N,μ-N1,μ-N2,N] (μ-dichloro)dichlorodicopper(II) ethanol,and 3,6-Bis(2-pyridylthio)-pyridazine

The X-ray structures of two binuclear copper(II) chloride complexes of the tetradentate ligands 1,4- bis(4,6-dimethyl-2-pyridylamino)phthalazine (PAP46Me) and 3,6-bis(2-pyridylthio)pyridazine are reported. [Cu₂(PAP46Me)Cl₄] (1) and [Cu₂(PTP)Cl₄]· CH₃CH₂OH (2) contain triply bridged binuclear centres involving a diazine (NN) and two chlorobridges with copper-copper separations in the fange 3.19–3.25 Å and distorted square pyramidal copper stereochemistry. The reduced room temperature magnetic moments indicate antiferromagnetically coupled binuclear copper(II) centres.Complex 1 forms green crystals with a= 15.795(3), b=10.661(3), c=16.155(4) Å, β= 113.82(3)°, C2/c, Z = 4, R_f=0.031. Complex (2) forms green crystals with a=33.9022(8), b= 9.1626(5), c= 15.7885(5) Å,β= 114.853(2)°, C2/c, Z=8, R_f=0.047. The structure of the ligand PTP is also reported and compared with that of 2.     

Ferromagnetic exchange coupling in the linear,chloride-bridged cluster (cyclam)CoII[(μ-Cl)UIV(Me2Pz)4]2

The trinuclear cluster (cyclam)Co[(μ-Cl)U(Me₂Pz)₄]₂ (cyclam = 1,4,8,11-tetraazacyclotetradecane, Me₂Pz^? = 3,5-dimethylpyrazolate) is synthesized through cleavage of the homoleptic dimer [U(Me₂Pz)₄]₂ by (cyclam)CoCl₂. A single crystal X-ray diffraction analysis reveals a linear chloride-bridged structure analogous to that previously reported for (cyclam)M[(μ-Cl)U(Me₂Pz)₄]₂ (M = Ni, Cu, Zn). The magnetic exchange coupling of the CoU₂ cluster was probed by analyzing the temperature dependence of its magnetic susceptibility. Comparison of χ_MT versus T between the CoU₂ species and the diamagnetic ZnU₂ cluster demonstrates the presence of ferromagnetic coupling between the Co^II and U^IV centers. We present methods for estimating upper and lower bounds for the exchange interaction energy in such systems and find that for CoU₂, the exchange constant, J, lies in the range 15–48 cm^?1. Application of these methods to the previously reported NiU₂ cluster suggests somewhat weaker ferromagnetic exchange, with J lying in the range 2.8–19 cm^?1. AC magnetic susceptibility experiments were not indicative of single-molecule magnet behavior for the CoU₂ cluster, although qualitative interpretation of the low-temperature magnetization data suggests the presence of significant zero-field splitting in the ground state.     

2-Phenyl and 2-heterocyclic-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridines as inhibitors of TGF-β1 and activin A signalling

Novel inhibitors of TGF-β1 and activin A signalling based on a 2-aryl-4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)pyridine pharmacophore have been synthesised. Compounds containing phenyl or aromatic nitrogen heterocycle substituents inhibited both types of signalling with HEK-293T cells in culture, with a selectivity preference for TGF-β1. Synthetic compounds containing pyridin-3-yl, pyrazol-4-yl, pyrazol-1-yl or 1H-imidazoyl-1-yl substituents exhibited structural and functional attributes suitable for further investigation related to the development of more potent TGF-β inhibitors.     

(S)-3-(4-(2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)-2-(piperazin-1-yl)propanoic acid compounds: Synthesis and biological evaluation of dual PPARα/γ agonists

A series of novel, potent PPARα/γ dual agonists were synthesized and appraised. The most potent analogue, compound 2b demonstrated EC₅₀ value of 0.012 ± 0.002 and 0.032 ± 0.01 μM, respectively, for hPPARα and hPPARγ in transactivation assay. Additionally, compound 2b demonstrated good glucose and lipid lowering effect in genetic diabetic (db/db) mice.     

Absorption of the biomimetic chromium cation triaqua-μ3-oxo-μ-hexapropionatotrichromium(III) in rats

The cation [Cr₃O(O₂CCH₂CH₃)₆(H₂O)₃]⁺ has been shown in vitro to mimic to the oligopeptide chromodulin’s ability to stimulate the tyrosine kinase activity of insulin receptor and shown in healthy and type 2 diabetic model rats to increase insulin sensitivity and decrease plasma total and low-density lipoprotein cholesterol and triglycerides concentrations. However, the degree to which the complex is absorbed after gavage administration to rats had not been previously determined. The biomimetic cation at nutritional supplement levels is absorbed with greater than 60% efficiency, and at pharmacological levels, it is absorbed with greater than 40% efficiency, an order of magnitude greater absorption than that of CrCl₃, Cr nicotinate, or Cr picolinate, currently marketed nutritional supplements. The difference in degree of absorption is readily explained by the stability and solubility of the cation.     

Synthesis and structure of the complex tetra-μ-prolinatodirhodium(II)

The dinuclear Rh^IIRh^II complex with proline [Rh₂(pro₄][NEt₄]₂ was synthesized and its structure studied by means of spectroscopic (IR, EPR and ESCA) and magnetochemical methods. It was shown that two proline molecules serve as bridging ligands, while the other two are only axially coordinated through their N atoms.     

Formation of ε-(2-Formyl-5-hydroxy-methyl-pyrrol-1-yl)-l-norleucine in the Maillard Reaction between d-Glucose and l-Lysine

An exo-β-1,3-glucanase was purified from the commercial enzyme preparation “Kitalase” which is a yeast cell wall lytic enzyme preparation. The purification procedures consisted of following steps: ammonium sulfate fraction, SP-Sephadex C-50 and CM-Cellulose C-32 column chromatography, and Sephadex G-100 gel filtration. The optimum pH value was 5.8, and the optimum temperature was 55°C. The enzyme was stable in the pH range of 5.1 to 9.8 and at temperatures below 53°C. The isoelectric point and the molecular weight were estimated to be pH 9.3 and 73000, respectively. The enzyme was shown to bypass β-1,6-linkaged branches to cleave β-1,3-linkages when scleroglucan was used as substrate. The Km values for laminariri, laminari-pentaose, laminaritetraose and laminaritriose were 0.16, 2.01, 2.24 and 1.34 mM, respectively.     

Synthesis of [{Os3(CO)10(μ2-H)}2{μ2,μ2-NC6H4C6H4N}] and [{Os3(CO)9(μ2-H)PPh3}2{μ2,μ2-NC6H4C6H4N}]: Carbon–carbon bond formation promoted by organorhodium species

Synthesis and characterization of linked cluster [{Os₃(CO)₁₀(μ₂-H)}₂{μ₂,μ₂-NC₆H₄C₆H₄N}] (1) from the reaction of [Os₃Rh(μ-H)₃(CO)₁₂] with aniline in the presence of an excess amount of 4-vinyl phenol in refluxing heptane is reported. A similar reaction with [Os₃(CO)₁₀(NCMe)₂] as starting material gave a known compound, [Os₃(CO)₁₀(μ₂-H)(μ₂-HNC₆H₅)] (2). The treatment of complexes 1 and 2 with Wilkinson’s catalyst in refluxing heptane respectively, yielded [{Os₃(CO)₉(μ₂-H)PPh₃}₂{μ₂,μ₂-NC₆H₄C₆H₄N}] (3). An interesting and unexpected C–C coupling of phenyl-amido ligands was observed in complexes 1 and 3, which is believed to be catalysed by the organometallic rhodium species. The newly synthesized compounds 1 and 3 were fully characterized by IR, ¹H NMR spectroscopy, mass spectroscopy, elemental analysis, and X-ray crystallography. Both structures 1 and 3 comprise two triangles of osmium atoms. The two triangular osmium metal cores are linked by a bi-amido ligand via the two nitrogen atoms N(1) and N(1)* and N(1) and N(2), at their equatorial sites. The electronic absorption spectra of complexes 1, 2, and 3 display both low energy absorption, dπ (Os) → π* (amido) metal-to-ligand charge-transfer (MLCT) transition, and π → π* intra-ligand electronic transitions of the amido and bi-amido ligands.     

Synthesis and evaluation of 6-(11C-methyl(4-(pyridin-2-yl)thiazol-2-yl)amino)benzo[d]thiazol-2(3H)-one for imaging γ-8 dependent transmembrane AMPA receptor regulatory protein by PET

Transmembrane AMPA receptor regulatory proteins (TARPs) are a recently discovered family of proteins that modulate AMPA receptors activity. Based on a potent and selective TARP subtype γ-8 antagonist, 6-(methyl(4-(pyridin-2-yl)thiazol-2-yl)amino)benzo[d]thiazol-2(3H)-one (compound 9), we perform the radiosynthesis of its ¹¹C-isotopologue 1 and conduct preliminary PET evaluation to test the feasibility of imaging TARP γ-8 dependent receptors in vivo.     

Preparation and optimization of new 4-(morpholin-4-yl)-(6-oxo-1,6-dihydropyrimidin-2-yl)amide derivatives as PI3Kβ inhibitors

From a HTS campaign, a new series of pyrimidone anilides exemplified by compound 1 has been identified with good inhibitory activity for the PI3Kβ isoform. The structure of compound 1 in PI3Kγ was solved revealing a binding mode in agreement with the SAR observed on PI3Kβ. These compounds displayed inhibition in the nanomolar range in the biochemical assay and were also potent p-Akt inhibitors in a PTEN-deficient PC3 prostate cancer cell line. Optimization of in vitro pharmocokinetic properties led to compound 25 exhibiting 52% bioavailability in mice and target engagement in an acute PK/PD study.     

Binuclear rhodium carbonyl halide complexes containing the 1,1-bis(diphenylphosphino)ethene ligand,and the crystal structure of [Rh2Cl2(μ-CO){Ph2PC(CH2)PPh2}2]

Treatment of [RhCl(CO)₂]₂ with 1,1-bis(diphenylphosphino)ethene (dppee) yields the cationic binuclear rhodium complex [Rh₂(μ-Cl)(CO)₂(μ-CO)(dppee)₂]⁺ which may be isolated as the [RhCl₂(CO)₂]⁻ salt at low temperature (230 K) but which readily forms the Cl⁻ salt on allowing the solution to warm to room temperature. On bubbling nitrogen through a solution of this cationic complex at room temperature, the monocarbonyl species, [Rh₂Cl₂(μ-CO)(dppee)₂] is obtained. The crystal structure of this complex has been determined. The crystals are orthorhombic, space group Pnca, a = 29.98(3), b = 23.70(2), c = 14.78(3) Å, Z = 8. Using 3019 unique reflections the structure was refined to R = 0.091. The rhodium-rhodium distance is 2.650(14) Å. Direct rhodium NMR data are reported for these complexes.     

Design,synthesis and biological activity evaluation of novel 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) oxy) pyridine-2-yl) amino derivatives as potent transforming growth factor-β (TGF-β) type I receptor inhibitors

TGF-β type I receptor (also known as activin-like kinase 5 or ALK5) plays a critical role in the progression of fibrotic diseases and tumor invasiveness and metastasis, as well. The development of small inhibitors targeting ALK5 has been validated as a potential therapeutic strategy for fibrotic diseases and cancer. Here, we developed various 4-((1-cyclopropyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl) oxy) pyridine-2-yl) amino derivatives as ALK5 inhibitors. The optimization led to identification of potent and selective ALK5 inhibitors 12r. The compound 12r exhibited strong inhibitory activity both in vitro and in vivo, and pharmacokinetics study showed an oral bioavailability of 57.6%. Thus, compound 12r may provide as new therapeutic option as ALK5 TGF-βR1 inhibitor.     

Identification of biaryl sulfone derivatives as antagonists of the histamine H₃ receptor: discovery of (R)-1-(2-(4'-(3-methoxypropylsulfonyl)biphenyl-4-yl)ethyl)-2-methylpyrrolidine (APD916)

The design of a new clinical candidate histamine-H(3) receptor antagonist for the potential treatment of excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were modified by replacement of the sulfonamide linkage with a sulfone. One compound from this series, 2j (APD916) increased wakefulness in rodents as measured by polysomnography with a duration of effect consistent with its pharmacokinetic properties. The identification of a suitable salt form of 2j allowed it to be selected for further development.