We have previously found that a pyrazole derivative 1 possesses antibacterial activity and inhibitory activity against DNA gyrase and topoisomerase IV. Here, we synthesized new pyrazole derivatives and found that 5-[(E)-2-(5-chloroindol-3-yl)vinyl]pyrazole 16 possesses potent antibacterial activity and selective inhibitory activity against bacterial topoisomerases. Many of the synthesized pyrazole derivatives were potent against clinically isolated quinolone- or coumarin-resistant Gram-positive strains and had minimal inhibitory concentration values against these strains equivalent to those against susceptible strains.

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1) This sub-classification has led to the development of b 1 -and b 2 -AR antagonists and/or agonists which have been useful for the treatment of cardiovascular diseases and asthma. In early 1980s, a third b-AR, initially referred to as "atypical"2) and later called b 3 -AR has been found in a number of species, including man, [3][4][5][6] and in 1989, the human, 7) rat, 8) and mouse 9) b 3 -ARs were first cloned and characterized. Like other b-ARs, b 3 -ARs belong to the G-protein-coupled receptor family that includes receptors with a common structure consisting of seven transmembrance-spanning connected by interhelical loops.10) The b 3 -AR is located on the surface of both white and brown adipocytes and is known to be stimulated by endogenous catecholamines, adrenalin, and noradrenaline. It has also been reported that b 3 -AR receptor plays a significant role in regulating lipolysis and thermogenesis in rodent and human adipose tissues. 11,12) Moreover, studies of b 3 -AR mRNA demonstrated that, b 3 -ARs exist in human heart, gall bladder, gastrointestinal tract, prostate, and urinary bladder detrusor tissue in addition to adipocytes. [13][14][15][16] Since the discovery of b 3 -AR, a number of laboratories have been engaged in developing potent and selective b 3 -AR agonists for the treatment of various metabolic and gastrointestinal diseases such as obesity, non-insulin dependent (Type-II) diabetes, irritable bowel syndrome, and urinary frequency and incontinence. [17][18][19][20][21] Early b 3 -AR agonists (the "first generation" of potent and selective rat b 3 -AR agonists) such as BRL 37344 (BRL 35135), [22][23][24] CL 316243, [25][26][27] and SR 58611A, 28) having a 3-chlorophenyl moiety in the left-hand side (LHS) and a carboxylic acid or an ester functionality in the right-hand side (RHS) as shown in Chart 1, have been reported to be effective anti-obesity and anti-diabetic agents in rodents.29) These compounds, through their potent agonistic activity for the b 3 -AR, stimulate lipolysis and energy expenditure and cause only a slight increase in heart rate (b 1 -AR activity) and weak muscle tremor (b 2 -AR activity). Unfortunately, some of these early b 3 -AR agonists developed for the treatment of metabolic disorders failed to produce similar effects in humans, due to a lack of selectivity and/or potency, or poor pharmacokinetics.30) Because of structural differences between human and rat b 3 -ARs with regard to the amino acid sequences of each receptor, activity at the rat b 3 -AR could not effectively predict that at the human b 3 -AR.31) Thus, a new generation of human b 3 -AR agonists with minimal side effects associated with activation of human b 1 -and b 2 -ARs has long been needed.A new generation of b 3 -AR agonists currently under preclinical development is represented by the tetrahydroisoquinoline 1, [32][33][34] SB 226552, 35,36) L 755507, 37) L 770644, 38,39) and LY-377604 40) (Chart 1). These compounds having both potent and full agonistic activity, and high selectivity at the human b...