A series of 12- to 22-membered macrocycles, with druglike functionality and properties, have been generated by using a simple and efficient copper-catalyzed azide-acetylene cycloaddition reaction, conducted in flow in high-temperature copper tubing, under environmentally friendly conditions. The triazole-containing macrocycles have been generated in up to 90 % yield in a 5 min reaction, without resorting to the high-dilution conditions typical of macrocyclization reactions. This approach represents a very efficient method for constructing this important class of molecules, in terms of yield, concentration, and environmental considerations.

A novel series of potent and selective sulfonamide derived β(2)-adrenoreceptor agonists are described that exhibit potential as inhaled ultra-long-acting bronchodilators for the treatment of asthma and chronic obstructive pulmonary disease. Analogues from this series mediate very long-lasting smooth muscle relaxation in guinea pig tracheal strips. The sulfonamide agonist headgroup confers high levels of intrinsic crystallinity that could relate to the acidic sulfonamide motif supporting a zwitterionic form in the solid state. Optimization of pharmacokinetic properties was achieved through targeted introduction of a phenolic moiety to support rapid phase II clearance, thereby minimizing systemic exposure following inhalation and reducing systemically mediated adverse events. Compound 38 (PF-610355) is identified as a clinical candidate from this series, with in vivo duration of action studies confirming its potential for once-daily use in humans. Compound 38 is currently in advanced phase II clinical studies.

6-Cyclohexyl-N-hydroxy-3-(1,2,4-oxadiazol-5-yl)hexanamides were previously disclosed as inhibitors of procollagen C-proteinase (PCP) culminating in the identification of amide 1. Our objective was to discover a second inhibitor that would have improved affinity for PCP and to optimize properties for transepidermal delivery (TED) to intact skin. Further investigation of this template identified a number of potent PCP inhibitors (IC50 values of 2-6 nM) with improved TED flux. Sulfonamide 56 had excellent PCP enzyme activity when measured with a peptide substrate (Ki 8.7 nM) or with the endogenous substrate procollagen (IC50 3.4 nM) and demonstrates excellent selectivity over MMPs involved in wound healing (>10 000-fold). In the fibroplasia model, 56 inhibited deposition of insoluble collagen by 76 +/- 2% at 10 microM and was very effective at penetrating human skin in vitro with a TED flux of 1.5 microg/cm2/h, which compares favorably with values for agents that are known to penetrate skin well in vivo. Based on this profile, 56 (UK-421,045) was selected as a candidate for further preclinical evaluation as a topically applied, dermal anti-scarring agent.

A highly efficient macrocyclization reaction has been developed via the palladium-catalyzed C-H arylation of the side-chains of tryptophan with halophenyl-containing amino acids. This method allows for direct access to 15- to 25-membered biaryl macrocycles in 40-75% yield, at moderate concentration, with C-H arylation proceeding exclusively at the C-2 position of the tryptophan indole.

The organozinc reagent 13, prepared from the protected ¡9-iodo alanine derivative 3c using ultrasonic activation, is efficiently acylated using acid chlorides in the presence of bis(triphenylphosphine)palladium dichloride to give enantiomerically pure protected 4-oxo-a-amino acids 17 in 39-90% yield (13 examples). Zinc reagent 13 can also be coupled with aryl iodides in the presence of bis(tri-o-tolylphosphine)palladium dichloride to give enantiomerically pure protected phenylalanine analogues 26,29, and 30 in 10-67% yield (11 examples). The reaction tolerates the presence of a variety of functional groups in the acid chloride and the aryl iodide and provides derivatives which can be easily deprotected, at either the carboxyl or amino terminus, to give intermediates suitable