Compound scale-up at the discovery-development interface.

As a result of an economically challenging environment within the pharmaceutical industry, pharmaceutical companies and their departments must increase productivity and cut costs to stay in line with the market. Discovery-led departments such as the medicinal chemistry and lead optimization groups focus on synthesizing large varieties of compounds in minimal amounts, while the chemical development groups must then deliver a few chosen leads employing an optimized synthesis method and using multi-kilogram quantities of material. A research group at the discovery-development interface has the task of medium-scale synthesis which is important in the lead selection stage. The primary objective of this group is the initial scale-up of promising leads for extensive physicochemical and biological testing. The challenge of the interface group involves overcoming synthetic issues within the rigid, accelerated timelines.

Pyridone-conjugated monobactam antibiotics with gram-negative activity.

Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa , Klebsiella pneumoniae , and Escherichia coli . Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1.

RFI-641, a potent respiratory syncytial virus inhibitor.

Human respiratory syncytial virus (RSV), a paramyxovirus, is a major cause of acute upper and lower respiratory tract infections in infants, young children, and adults. RFI-641 is a novel anti-RSV agent with potent in vitro and in vivo activity. RFI-641 is active against both RSV type A and B strains. The viral specificity and the large therapeutic window of RFI-641 (>100-fold) indicate that the antiviral activity of the compound is not due to adverse effects on normal cells. The potent in vitro activity of RFI-641 can be translated to efficacy in vivo: RFI-641 is efficacious when administered prophylactically by the intranasal route in mice, cotton rats, and African green monkeys. RFI-641 is also efficacious when administered therapeutically (24 h postinfection) in the monkey model. Mechanism of action studies indicate that RFI-641 blocks viral F protein-mediated fusion and cell syncytium formation.