Pharmacokinetics and whole-blood bactericidal activity against Mycobacterium tuberculosis of single doses of PNU-100480 in healthy volunteers.

BACKGROUND: The oxazolidinone PNU-100480 is superior to linezolid against experimental murine tuberculosis. Two metabolites contribute to but do not fully account for its superiority. This study examined the safety, tolerability, pharmacokinetics, and mycobactericidal activity of single ascending doses of PNU-100480. METHODS: Nineteen healthy volunteers received 2 escalating single oral doses (35-1500 mg) of PNU-100480 or placebo. Eight subjects received 4 daily doses of 300 mg of linezolid. Drug concentrations and bactericidal activity against Mycobacterium tuberculosis in whole-blood bactericidal culture were measured. RESULTS: All doses were safe and well tolerated. PNU-100480 doses to 1000 mg were well absorbed and showed approximately proportional increases in exposures of parent and metabolites. The geometric mean maximal concentrations of PNU-100480, PNU-101603, and PNU-101244 (sulfoxide and sulfone metabolites) at 1000 mg were 839, 3558, and 54 ng/mL, respectively. The maximal whole-blood bactericidal activity (-0.37 +/- .06 log/day) occurred at combined PNU levels > or =2 times the minimum inhibitory concentration. The observed geometric mean maximal concentration for linezolid was 6425 ng/mL. Its maximal whole-blood bactericidal activity also occurred at > or =2 times the minimum inhibitory concentration, but it was only -0.16 +/- .05 log/day (P< .001) Neither drug showed enhanced activity at higher concentrations. CONCLUSIONS: Single doses of PNU-100480 to 1000 mg were well tolerated and exhibited antimycobacterial activity superior to 300 mg of linezolid at steady state. Additional studies are warranted to define its role in drug-resistant tuberculosis.

Human sebum requires de novo lipogenesis, which is increased in acne vulgaris and suppressed by acetyl-CoA carboxylase inhibition.

Sebum plays important physiological roles in human skin. Excess sebum production contributes to the pathogenesis of acne vulgaris, and suppression of sebum production reduces acne incidence and severity. We demonstrate that sebum production in humans depends on local flux through the de novo lipogenesis (DNL) pathway within the sebocyte. About 80 to 85% of sebum palmitate (16:0) and sapienate (16:1n10) were derived from DNL, based on stable isotope labeling, much higher than the contribution of DNL to triglyceride palmitate in circulation (~20%), indicating a minor contribution by nonskin sources to sebum lipids. This dependence on local sebocyte DNL was not recapitulated in two widely used animal models of sebum production, Syrian hamsters and Göttingen minipigs. Confirming the importance of DNL for human sebum production, an acetyl-CoA carboxylase inhibitor, ACCi-1, dose-dependently suppressed DNL and blocked synthesis of fatty acids, triglycerides, and wax esters but not free sterols in human sebocytes in vitro. ACCi-1 dose-dependently suppressed facial sebum excretion by ~50% (placebo adjusted) in human individuals dosed orally for 2 weeks. Sebum triglycerides, wax esters, and free fatty acids were suppressed by ~66%, whereas non-DNL-dependent lipid species, cholesterol, and squalene were not reduced, confirming selective modulation of DNL-dependent lipids. Last, individuals with acne vulgaris exhibited increased sebum production rates relative to individuals with normal skin, with >80% of palmitate and sapienate derived from DNL. These findings highlight the importance of local sebocyte DNL for human skin sebaceous gland biology and illuminate a potentially exploitable therapeutic target for the treatment of acne vulgaris.

In vitro microbiological characterization of a novel azalide, two triamilides and an azalide ketal against bovine and porcine respiratory pathogens.

Several novel 15-membered-ring macrolide agents (azalide 1, triamilides 2 and 3, and the azalide 3,6-ketal 4) were identified as potential antibacterial agents against Mannheimia (formerly named as Pasteurella) haemolytica, Pasteurella multocida, Haemophilus somnus and Actinobacillus pleuropneumoniae, important etiological agents of bovine and porcine respiratory disease. Compound 3 is the major component of the antibiotic tulathromycin. Antibacterial activity against tilmicosin-resistant P. multocida field isolates was also tested. In vitro MIC 50/90 analysis revealed that the four newly synthesized compounds were more potent than tilmicosin against M. haemolytica (4 to approximately 8x), P. multocida (8 to approximately 16x), A. pleuropneumoniae (4x), H. somnus (2x and 16x), and tilmicosin-resistant P. multocida (32x). In time-kill kinetic studies, all four novel compounds and tilmicosin showed bactericidal activity against M. haemolytica, P. multocida and A. pleuropneumoniae at both 4x and 8x MIC. A functional assay using genetically defined mutants revealed that all four novel compounds were poorer substrates for the efflux pump, AcrA/B system, than tilmicosin. A pH study using LPS mutants indicated that the enhanced in vitro potency of the triamilides, particularly compound 3 was mainly due to better penetration of the molecule through the outer membrane. The third amine group at the C-4'' position of the triamilde molecules contributed to this increased membrane penetration by increasing overall basicity. These studies indicate that the four novel compounds have potential as antibacterial agents against bovine and porcine respiratory disease.

5-Heteroatom-substituted pyrazoles as canine COX-2 inhibitors: Part 2. Structure-activity relationship studies of 5-alkylethers and 5-thioethers.

Structure-activity relationship (SAR) studies of novel 2-[3-trifluoromethyl-5-alkyl(thio)ether pyrazo-1-yl]-5-methanesulfonyl pyridine derivatives for canine COX enzymes are described. The 4-cyano-5-alkyl ethers were found to have excellent potency and selectivity, whereas the 5-thioethers were potent but less selective than the ether analogs in a canine whole blood (CWB) COX-2 assay.

5-heteroatom substituted pyrazoles as canine COX-2 inhibitors. Part 1: Structure-activity relationship studies of 5-alkylamino pyrazoles and discovery of a potent, selective, and orally active analog.

Structure-activity relationship (SAR) studies of the novel 2-[3-di and trifluoromethyl-5-alkylamino pyrazo-1-yl]-5-methanesulfonyl (SO(2)Me)/sulfamoyl (SO(2)NH(2))-pyridine derivatives for canine COX enzymes are described. The studies led to the identification of 2e as lead with potent in vitro activity, selectivity, and in vivo activity in dogs and cats.

Synthesis and SAR of heteroaryl-phenyl-substituted pyrazole derivatives as highly selective and potent canine COX-2 inhibitors.

The discovery of heteroaryl-phenyl-substituted pyrazole derivatives as canine selective COX-2 inhibitors is described. Structure-activity relationship (SAR) studies of this class of compounds led to the identification of compound 1 which demonstrated a canine whole blood COX-2 inhibitory IC50 of 12 nM and selectivity ratio of COX-1/COX-2 greater than 4000-fold.