Letters in Drug Design & Discovery - Volume 2, Issue 7, 2005

A series of novel bicyclic proline P2 scaffold based tetrapeptide inhibitors were designed and prepared. Given their relatively small size, these compounds exhibited exceptional binding affinities and good cellular potencies for HCV protease. One of the best analogues, tricyclic based P2 scaffold 12, had an affinity for HCV with a Ki of 37 nM and cell activity IC50 of 200 nM.

Ximelagatran is a prodrug that is rapidly converted to melagatran, a direct, competitive and reversible inhibitor of the active site of human α-thrombin. Its effect is independent from diet, plasma antithrombin levels, obesity or ethnicity. It has little effect on bleeding time at doses up to twice those required, and interference with other drugs is avoided by the absence of interaction with cytochrome P450. Ximelagatran h Read More

Selective inhibitors of tyrosine kinase 2 (Tyk2) were searched for using database screening, de novo ligand design and computational docking in Tyk2 and seven other protein kinases. None of the structures in the National Cancer Institute database seem to inhibit Tyk2 selectively, but five of the designed structures seem promising.

The p38 mitogen-activated protein kinase (MAPK) plays an essential role in the normal inflammatory response, however chronic activation of p38 can lead to the development of inflammatory diseases. Several small molecule p38 inhibitors have been developed for the treatment of inflammatory diseases. These inhibitors are used extensively for understanding the requirements for p38 activity in many cellular proce Read More

A quantitative structure-activity relationship (QSAR) study has been made on some bicyclic heteroaryl hydroxamic acid analogs acting as matrix metalloproteinase (MMP) inhibitors. The inhibition potencies of compounds against a number of MMPs were subjected to QSAR analysis and it was found surprisingly that the most crucial property of the molecules controlling the drug action, the hydrophobicity, to be playing a negativ Read More

A series of tetrasubstituted pyrrole derivatives, structurally related to tyrosine kinase inhibitors, has been synthesized one-pot by irradiation of a silica gel absorbed mixture of a conjugated alkynoate and a primary amine. The compounds were evaluated for their anticancer activities using the human breast cancer cell lines, T-47D and MCF7.

Luteinizing hormone-releasing hormone (GnRH) antagonists competitively block pituitary GnRH receptors, thus leading to an immediate decrease of the circulating levels of follicle stimulating hormone (FSH) and luteinizing hormone (LH) and consequently of sex steroids. They are clinically used when pharmacologically induced hormone suppression is desired, e.g. in sex steroid dependent benign and malignant diseases and for p Read More

The synthesis of some steroidal dioximes (22-29) and their in vitro antineoplastic activity are described in this report. The oximino functionality was incorporated at position 3 and 17 of the 16- benzylidene substituted steroidal nucleus to study the importance of dioximino moiety on anticancer activity. The synthesized compounds were screened for their in vitro antitumor activity against the cell panel consisting of three lines (br Read More

The patients' psychiatric diagnoses play a large role in the design and outcome of psychopharmacology clinical trials. Among antidepressant trials, magnitude of placebo response, initial severity of depression, dosing regimen, number of treatment arms and duration of trial, choice of rating scales, and sex of the patient may influence antidepressant trial outcome.

Numerous studies have shown that nicotinamide can prevent cell death via both necrosis and apoptosis. DNA fragmentation, NAD, poly(ADP-ribose) polymerase, apoptosis inducing factors, tumor necrosis factors, p53, caspases, inhibitor of apoptosis proteins and other factors are important in the action of nicotinamide. In this review, the regulatory effect of nicotinamide on individual pro- and anti-apoptotic proteins in neuronal cell Read More

L-dopa is the most effective drug in the symptomatic management of PD and extends the life span of PD patients.The question whether L-dopa is neurotoxic remains however unresolved. In recent years, increased Homocysteine (Hcy) levels have been observed in L-dopa treated Parkinson's disease (PD) patients, resulting from L-dopa O-methylation by the enzyme catechol-O-methyltransferase. This review summarizes curre Read More

A series of eight N'-[(E)-(disubstituted-phenyl)methylidene]isonicotino-hydrazide derivatives were synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis, and the activity expressed as the minimum inhibitory concentration (MIC) in mg/mL. Four compounds 2b-d and 2f exhibited a significant activity (0.6 mg/mL), when compared with first line drugs such as isoniazid (INH) and rifa Read More

Renal elimination of drugs bound to plasma proteins is mediated mainly by tubular secretion. Furosemide, a frequently used diuretic, is tightly bound to plasma proteins and is believed to be secreted. It contains a carboxyl group and a sulfamoyl moiety and may therefore be a substrate for the sodium-dependent dicarboxylate cotransporter from human kidney (hNaDC-3). Furosemide, besides inhibiting [14C]succinate uptake Read More