Redox-neutral α,ß-difunctionalization of cyclic amines.

In contrast to the continuously growing number of methods that allow for the efficient α-functionalization of amines, few strategies exist that enable the direct functionalization of amines in the ß-position. A general redox-neutral strategy is outlined for amine ß-functionalization and α,ß-difunctionalization that utilizes enamines generated in situ. This concept is demonstrated in the context of preparing polycyclic N,O-acetals from simple 1-(aminomethyl)-ß-naphthols and 2-(aminomethyl)-phenols.

Redox-neutral α-arylation of amines.

The direct α-arylation/N-alkylation of cyclic amines was achieved in a redox-neutral fashion under mild conditions. Transformations occur in the absence of any additives or are promoted by simple carboxylic acids.

Discovery of N-(4'-(indol-2-yl)phenyl)sulfonamides as novel inhibitors of HCV replication.

A series of novel 2-phenylindole analogs were synthesized and evaluated for activity in subgenomic HCV replicon inhibition assays. Several compounds containing small alkyl sulfonamides on the phenyl ring exhibiting submicromolar EC50 values against the genotype 1b replicon were identified. Among these, compound 25d potently inhibited the 1b replicon (EC50=0.17 µM) with 147-fold selectivity with respect to cytotoxicity. Compound 25d was stable in the presence of human liver microsomes and had a good pharmacokinetic profile in rats with an IV half-life of 4.3h and oral bioavailability (F) of 58%.

Dihydropyridopyrazinones and dihydropteridinones as corticotropin-releasing factor-1 receptor antagonists: structure-activity relationships and computational modeling.

The CRF antagonist pharmacophore is a heterocyclic ring bearing a critical hydrogen-bond acceptor nitrogen and an orthogonal aromatic ring. CRFR1 antagonists have shown a 40-fold and 200-fold loss in potency against the CRFR1 H199V and M276I mutant receptors, suggesting key interactions with these residues. We have derived a two component computational model that correlates CRFR1 binding affinity within the reported series to antagoinst/H199 complexation energy and M276 hydrophobic contacts.

PTC124 targets genetic disorders caused by nonsense mutations.

Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.

Imidazo[4,5-b]pyridines as corticotropin releasing factor receptor ligands.

A series of high affinity CRF receptor ligands with an imidazo[4,5-b]pyridine core is described. Individual analogues were synthesized and tested in a rat CRF receptor binding assay. The best compounds were further tested in the dog N-in-1 pharmacokinetic model to assess plasma levels at 1mg/kg (po) and in the rat situational anxiety model to assess anxiolytic efficacy at 3mg/kg (po). The structure-activity relationships for good receptor binding affinity are described herein.

Imidazo[4,5-c]pyridines as corticotropin releasing factor receptor ligands.

A series of high affinity CRF receptor ligands with an imidazo[4,5-c]pyridine core is described. Individual analogues were synthesized and tested in vitro in rat brain receptors to determine binding affinity. The best compound was further tested in the dog N-in-1 pharmacokinetic model to assess oral bioavailability at 1 mg/kg po.

One hundred US EVAs: a perspective on spacewalks.

In the 36 years between June 1965 and February 2001, the US human space flight program has conducted 100 spacewalks, or extravehicular activities (EVAs), as NASA officially calls them. EVA occurs when astronauts wearing spacesuits travel outside their protective spacecraft to perform tasks in the space vacuum environment. US EVA started with pioneering feasibility tests during the Gemini Program. The Apollo Program required sending astronauts to the moon and performing EVA to explore the lunar surface. EVA supported scientific mission objectives of the Skylab program, but may be best remembered for repairing launch damage to the vehicle and thus saving the program. EVA capability on Shuttle was initially planned to be a kit that could be flown at will, and was primarily intended for coping with vehicle return emergencies. The Skylab emergency and the pivotal role of EVA in salvaging that program quickly promoted Shuttle EVA to an essential element for achieving mission objectives, including retrieving satellites and developing techniques to assemble and maintain the International Space Station (ISS). Now, EVA is supporting assembly of ISS. This paper highlights development of US EVA capability within the context of the overarching mission objectives of the US human space flight program.