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.

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. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.

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. The identification of the metabolites enabled the preparation of two optimized compounds 13 and 14 that were devoid of the metabolic liabilities associated with 1. Compounds 13 and 14 are potent dual A(2A)/A(1) receptor antagonists that have excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse and rat models of reserpine-induced akinesia, and the rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation.

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 30.5%. Compound 1 is a potent A(2A)/A(1) receptor antagonist in vitro (A(2A) K(i) = 4.1 nM; A(1) K(i) = 17.0 nM) that has excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse model of reserpine-induced akinesia, rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation, and MPTP-treated non-human primate model.

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) = 0.79 nM), which has approximately 20-fold greater affinity for NS5B than its carbonyl analogue (R)-2c.

A novel metal-organic ternary topology constructed from triangular, square and tetrahedral molecular building blocks.

A novel metal-organic network [Cu(4)(5-NH(2)-1,3-bdc)(4)(pyridine)(2)(H(2)O)(2)](n), displaying an unprecedented topology has been constructed utilizing the different coordinating functional groups of 5-NH(2)-1,3-bdc to generate a ternary network based upon vertex-linked triangular, square and tetrahedral molecular building blocks (MBBs).

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...N interactions. This motif of second-sphere coordination for 1 can be exploited as a tool for crystal engineering. As a demonstration of the generality of this new interaction as a supramolecular building block, five X-ray crystal structures are reported that utilise this hydrogen bonding scheme; [Co(H2O)4(NO3)2].(1)2 (2a), [Co(MeCN)2(H2O)4][ClO4]2.(1)2 (2b), [Ni(H2O)4(NO3)2].(1)2 (3a), [Mn(H2O)4(NO3)2].(1)2 (4a), and [Mn(H2O)6][ClO4]2.(1)(4).4H2O (4b). Each network involves complete saturation of the hydrogen-bond donor sets between the aqua complex and 1 using primarily M-O-H...N(1) and M-O-H...O(anion), interactions. Thermogravimteric analysis shows these materials to have stabililities similar to coordination polymers involving metal-ligand bonds; this demonstrates that second-sphere hydrogen bonding has potential for the construction of polymeric metal-containing materials.