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.

Discovery of a stable macrocyclic o-aminobenzamide Hsp90 inhibitor which significantly decreases tumor volume in a mouse xenograft model.

An extension of our previously reported series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. Addition of a second methyl group to the tether provided analogs that show increased potency in binding as well as cell-proliferation assays and, more importantly, are stable toward microsomes. We wish to disclose the discovery of a macrocycle which showed impressive biomarker activity 24-h post dosing and which demonstrated prolonged exposure in tumors. When studied in a lung cancer xenograft model, the compound demonstrated significant tumor size reduction.

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.

Pyrimidine containing RSV fusion inhibitors.

The knowledge of SAR in a series of biphenyl anionic RSV inhibitors has been broadened by synthesis and testing of analogs with pyrimidine linkers. Generally, pyrimidine compounds were much harder to synthesize, and their anti-RSV activity was lower in comparison with triazine analogs.

Design and syntheses of 1,6-naphthalene derivatives as selective HCMV protease inhibitors.

Through high throughput screening of various libraries, substituted styryl naphthalene 6 was identified as an HCMV protease inhibitor. Optimization of various regions of the lead molecule using parallel synthesis resulted in 1,6-substituted naphthalenes 19d-i. These compounds displayed good potency and were selective over elastase, trypsin, and chymotrypsin. The optimization approach on lead compound 6 in three different regions of the molecule using parallel solution-phase synthesis and the corresponding SAR are discussed in detail.

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.