4-Methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridine-Based P2X7 Receptor Antagonists: Optimization of Pharmacokinetic Properties Leading to the Identification of a Clinical Candidate.

The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing.

Design and characterization of optimized adenosine A₂A/A₁ receptor antagonists for the treatment of Parkinson's disease.

The design and characterization of two, dual adenosine A(2A)/A(1) receptor antagonists in several animal models of Parkinson's disease is described. Compound 1 was previously reported as a potential treatment for Parkinson's disease. Further characterization of 1 revealed that it was metabolized to reactive intermediates that caused the genotoxicity of 1 in the Ames and mouse lymphoma L51784 assays.

In vivo characterization of a dual adenosine A2A/A1 receptor antagonist in animal models of Parkinson's disease.

The in vivo characterization of a dual adenosine A(2A)/A(1) receptor antagonist in several animal models of Parkinson's disease is described. Discovery and scale-up syntheses of compound 1 are described in detail, highlighting optimization steps that increased the overall yield of 1 from 10.0% to 30.

Structure-based design of a benzodiazepine scaffold yields a potent allosteric inhibitor of hepatitis C NS5B RNA polymerase.

HCV NS5B polymerase, an essential and virus-specific enzyme, is an important target for drug discovery. Using structure-based design, we optimized a 1,5-benzodiazepine NS5B polymerase inhibitor chemotype into a new sulfone-containing scaffold. The design yielded potent inhibitor (S)-4c (K(D) = 0.

Coordination polymers with 4,4'-bipyrimidine. Using a combination of endo- and exodentate donors to build a one-dimensional Ag(I) ladder and a heterometallic Co(II)Ag(I)2 network.

The ligand 4,4'-bipyrimidine combines a chelating bipyridine group and two terminal donor atoms into a single molecule; chelation to a single Ag(I) centre forms a square planar complex which can then form an extended planar ladder-type polymer by linking through linear Ag(I) centres whereas bis-coordination to an octahedral Co(II) centre yields a building block with four external donor nitrogen atoms which can coordinate to two distinct Ag(I) ions to form a heterometallic 2D net.

4-Connected metal-organic assemblies mediated via heterochelation and bridging of single metal ions: Kagome lattice and the M6L12 octahedron.

Single-metal-ion-based rigid molecular building blocks (MBBs) have been utilized to design and synthesize novel metal-organic assemblies. Reaction between In(NO3)3.2H2O and 2,5-pyridinedicarboxylic acid (2,5-H2PDC) has permitted the assembly of two supramolecular isomers, a Kagomé lattice and an unprecedented M6L12 discrete octahedron.

Hydrogen-bonded networks through second-sphere coordination.

The reaction of 4, 7-phenanthroline (1) with aqueous transitionmetal complexes [Mn(H2O)6][NO3]2, [Co(H2O)6][NO3]2, [Ni(H2O)6[NO3]2, [Mn(H2O)6][ClO4]2, and [Co(H2O)6][ClO4]2 does not produce coordination complexes between these metal cations and the N-donor ligand as expected. Instead, supramolecular hydrogenbonded networks are formed between the nitrogen donor atoms of 4, 7-phenanthroline and the OH groups of coordinated water molecules: M-O-H..