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Over 50 phenyl thiazolyl urea and carbamate derivatives were synthesized for evaluation as new inhibitors of bacterial cell-wall biosynthesis. Many of them demonstrated good activity against MurA and MurB and gram-positive bacteria including MRSA, VRE and PRSP. 3,4-Difluorophenyl 5-cyanothiazolylurea (3p) with clog P of 2.64 demonstrated antibacterial activity against both gram-positive and gram-negative bacteria.

Twenty-five 2-phenyl-5,6-dihydro-2H-thieno[3,2-c]pyrazol-3-ol derivatives were synthesized for evaluation as new inhibitors of bacterial cell wall biosynthesis. Many of them demonstrated good inhibitory activity against Staphylococcus aureus MurB, MurC and MurD enzymes in vitro and antimicrobial activity against gram-positive bacteria including MRSA, VRE and PRSP. However, when they were tested in the presence of 4% bovine serum albumin, the MIC values increased to greater than 128 microg/mL against PRSP. None of the compounds demonstrated activity against gram-negative bacteria at MIC

A series of xanthine sulfonamides is presented as a class of calcitonin (CT) inducers - a potentially new method for treating diseases associated with postmenopausal bone loss such as osteoporosis. We have found that certain di-n-butylxanthine sulfonamides 4 upregulate CT transcription in a CT-luciferase reporter gene assay (CT-luci) and increase the production and release of CT in a CT secretion/RIA assay (CTS). In addition, these compounds do not have potent PDE4 inhibitory activity as do the related xanthine methylene ketones such as denbufyllene (2). One compound in particular (9) shows a transcription activation ratio (TAR) of 2.1 in CT-luci, a CTS increase of 3.6-fold, and a PDE4 (phosphodiesterase type IV) IC(50) = 4.1 microM. In addition, this compound showed a statistically significant 47% trabecular bone protection in ovariectomized-induced osteopenia (OVX) rats as determined by assay when administered for 4 weeks at 30 mg/kg/day, i. p. by quantitative computed tomography (QCT). When administered p.o., compound 9 shows 50% trabecular bone protection when administered for 3 weeks at 50 mg/kg/day, i.p. This compared with salmon CT which shows 62% trabecular bone protection when administered at 50 IU/kg/day for 4 weeks.

CL316243 is a highly selective and potent β 3 -adrenergic receptor agonist, and has been shown in rodent models to be an effective agent for treating obesity and Type II diabetes. To improve the oral absorption and pharmacokinetic profiles of CL316243, a number of prodrugs have been synthesized and evaluated. Several ester-type prodrugs show significant improvements in oral bioavailability in both rodent and primate models.

A series of 5-arylpyrrolo[3,2-b]pyridines 1 was synthesized by addition of 3-aminopyrroles to aryl enaminones. One example of a 7-arylpyrrolo[3,2-b]pyridine 2 was obtained as a minor product along with the 5-aryl isomer, by a modification of the reaction sequence.

The synthesis and biological evaluation of a series of 2,3,6-substituted 4(3H)quinazolinones is described. One of these compounds, CL329, 167, was found to be a potent, orally active, competitive angiotensin II receptor antagonist with a long duration of action.

The synthesis of the novel 5-amino-8-phenyl-3H,6H-1,4,5a,8a-tetraazaacenaphthalen-3-one ring system has yielded several compounds which display activity in the reversal of cognition deficits in rats and mice as compared to existing reference agents. Activity was determined by improvements in Hypoxic Survival and Anoxic-Induced Amnesia tests. The synthesis and biological activity of the title compounds is described.

The synthesis and radioligand binding data of optically active hydroxylated oxotremorine derivatives are described. These are significant pharmacological differences between the enantiomers, most notably at the 3- and 4-position of the pyrrolidinone ring. In addition, there appears to be one side of the pyrrolidinone ring that accommodates substituents better than the other (facial selectivity).

The synthesis of the novel 5-amino-8-phenyl-3H,6H-1,4,5a,8a-tetraazaacenaphthalen-3-one ring system has yielded several compounds which display activity in the reversal of cognition deficits in rats and mice as compared to existing reference agents. Activity was determined by improvements in Hypoxic Survival and Anoxic-Induced Amnesia tests. The synthesis and biological activity of the title compounds is described.

Sixteen muraymycin derivatives 2-17 were synthesized based on selective reactions of the primary and secondary amino groups of muraymycin C1 (1) with isocyanates and aldehydes. Disubstituted derivatives 3-9 demonstrated no activity against either MraY or MurG at

A series of pyrazolo[4,3-d]pyrimidine sulfonamides and pyrazolo[3,4-d]pyrimidine sulfonamides have been synthesized. These compounds increase transcription of a calcitonin-luciferase promoter and production of cellular calcitonin in a calcitonin-secretion/RIA assay with minimized phosphodiesterase type 4 inhibitory activity at 30 microM as compared to structurally related xanthine methylene ketones such as denbufyllene. These two series are notable examples of small molecules that act as CT-inducers, a method to potentially treat bone loss diseases.

Two stereoselective processes for the synthesis of novel 3,6-disubstituted penam sulfone derivatives were developed. One 6beta-(1-hydroxyethyl) and four 6beta-hydroxymethyl penam sulfone derivatives were synthesized. All four 6beta-(hydroxymethyl)penam sulfone derivatives demonstrated good IC50 against both TEM-1 and AmpC beta-lactamases. Of these, 6beta-hydroxymethyl penam sulfone derivative 25 was the most active inhibitor which was able to restore the activity of piperacillin in vitro and in vivo against both TEM-1 and AmpC beta-lactamases producing organisms.

Five 6-(1-hydroxyalkyl)penam sulfone derivatives and two 6-(hydroxymethyl)penams were synthesized for beta-lactamase inhibitor screens. The substituent effects and stereochemical requirements of 6alpha- and 6beta-(1-hydroxyalkyl) groups for the biological activity of penam sulfone derivatives were investigated. Of these substituents, only the 6beta-hydroxymethyl group of 15 improved the activity of sulbactam against both TEM-1 and AmpC beta-lactamases. The sulfone moiety is required for the enhancement of the beta-lactamase inhibitory activity. 6Beta-hydroxymethylsulbactam (15) was able to restore the activity of piperacillin in vitro and in vivo against various beta-lactamase producing microorganisms.

2-Aminobenzimidazoles were reacted with enaminones in acetic acid to give pyrimido[1,2-a]benzimidazoles. With a substituted enaminone only one regioisomer was obtained. Structural assignments based on nmr and uv spectroscopy are presented. Possible pathways leading to the products are discussed.

2-Aminobenzimidazoles were reacted with enaminones in acetic acid to give pyrimido[1,2-a]benzimidazoles. With a substituted enaminone only one regioisomer was obtained. Structural assignments based on nmr and uv spectroscopy are presented. Possible pathways leading to the products are discussed.