Novel 3-fluoro-6-methoxyquinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV.

Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emerging class of antibacterial agents. We report an optimized series of cyclobutylaryl-substituted NBTIs. Compound 14 demonstrated excellent activity both in vitro (S.

Novel quinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV.

A structurally novel set of inhibitors of bacterial type II topoisomerases with potent in vitro and in vivo antibacterial activity was developed. Dual-targeting ability, hERG inhibition, and pharmacokinetic properties were also assessed.

Discovery, synthesis and SAR of azinyl- and azolylbenzamides antagonists of the P2X₇ receptor.

The discovery, of a series of 2-Cl-5-heteroaryl-benzamide antagonists of the P2X(7) receptor via parallel medicinal chemistry is described. Initial analogs suffered from poor metabolic stability and low Vd(ss). Multi parametric optimization led to identification of pyrazole 39 as a viable lead with excellent potency and oral bioavailability.

Optimization of the physicochemical and pharmacokinetic attributes in a 6-azauracil series of P2X7 receptor antagonists leading to the discovery of the clinical candidate CE-224,535.

High throughput screening (HTS) of our compound file provided an attractive lead compound with modest P2X(7) receptor antagonist potency and high selectivity against a panel of receptors and channels, but also with high human plasma protein binding and a predicted short half-life in humans. Multi-parameter optimization was used to address the potency, physicochemical and pharmacokinetic properties which led to potent P2X(7)R antagonists with good disposition properties. Compound 33 (CE-224,535) was advanced to clinical studies for the treatment of rheumatoid arthritis.

PF-03814735, an orally bioavailable small molecule aurora kinase inhibitor for cancer therapy.

The Aurora family of highly related serine/threonine kinases plays a key role in the regulation of mitosis. Aurora1 and Aurora2 play important but distinct roles in the G(2) and M phases of the cell cycle and are essential for proper chromosome segregation and cell division. Overexpression and amplification of Aurora2 have been reported in different tumor types, including breast, colon, pancreatic, ovarian, and gastric cancer.

Novel CCR1 antagonists with improved metabolic stability.

The synthesis, biological activity, and pharmacokinetic profile of novel CCR1 antagonists are described.

Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor.

Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease.

Flavin-containing monooxygenase activity in hepatocytes and microsomes: in vitro characterization and in vivo scaling of benzydamine clearance.

Liver microsomes, and more recently cryopreserved hepatocytes, are commonly used in the in vitro characterization of the metabolism of new xenobiotics. The flavin-containing monooxygenases (FMO) are a major non p450 oxidase present in liver microsomes and hepatocytes. Since FMO is known to be thermally labile, and this enzyme may be involved in the metabolic clearance of some drugs, we sought to more completely characterize the metabolic competency of this enzyme in cryopreserved hepatocytes and in liver microsomes preincubated under various conditions using benzydamine as an in vitro and in vivo probe.