Phenylindenone isomers as divergent modulators of p38α MAP kinase.

Two new fluorophenylindenone derivatives were designed as potential p38α MAPK modulators by preserving the key interactions of the vicinal pyridine/fluorophenyl pharmacophore with the enzyme protein. Interestingly, these two fluorophenylindenone isomers showed divergent activities, with compound 6 behaving as an inhibitor and 5 as a putative activator. These results were rationalized by docking studies and molecular dynamics simulations in terms of stabilization of DFG loop, by compound 5 in a conformation more accessible to phosphorylation.

Ipilimumab experience in heavily pretreated patients with melanoma in an expanded access program at the University Hospital of Siena (Italy).

AIM OF STUDY: To evaluate the feasibility of ipilimumab treatment for metastatic melanoma outside the boundaries of clinical trials, in a setting similar to that of daily practice. METHODS: Ipilimumab was available upon physician request in the Expanded Access Programme for patients with life-threatening, unresectable stage III/IV melanoma who failed or did not tolerate previous treatments and for whom no therapeutic option was available. Induction treatment with ipilimumab 10 mg/kg was administered intravenously every 3 weeks, for a total of 4 doses, with maintenance doses every 12 weeks based on physicians' discretion and clinical judgment. Tumors were assessed at baseline, Week 12, and every 12 weeks thereafter per mWHO response criteria, and clinical response was scored as complete response (CR), partial response (PR), stable disease (SD), or progressive disease. Durable disease control (DC) was defined as SD at least 24 weeks from the first dose, CR, or PR. RESULTS: Disease control rate at 24 and 60 weeks was 29.6% and 15%, respectively. Median overall survival at a median follow-up of 8.5 months was 9 months. The 1- and 2-year survival rates were 34.8% and 23.5%, respectively. Changes in lymphocyte count slope and absolute number during ipilimumab treatment appear to correlate with clinical response and survival, respectively. Adverse events were predominantly immune related, manageable, and generally reversible. One patient died from pancytopenia, considered possibly treatment related. CONCLUSION: Ipilimumab was a feasible treatment for malignant melanoma in heavily pretreated, progressing patients. A sizeable proportion of patients experienced durable DC, including benefits to long-term survival.

Design, synthesis, and biological evaluation of AT1 angiotensin II receptor antagonists based on the pyrazolo[3,4-b]pyridine and related heteroaromatic bicyclic systems.

Novel AT 1 receptor antagonists bearing the pyrazolo[3,4- b]pyridine bicyclic heteroaromatic system (or structurally related moieties) were designed and synthesized as the final step of a large program devoted to the development of new antihypertensive agents and to the understanding of the molecular basis of their pharmacodynamic and pharmacokinetic properties. The preliminary pharmacological characterization revealed nanomolar AT 1 receptor affinity for several compounds of the series and a potent antagonistic activity in isolated rabbit aortic strip functional assay for 7c and 8a. These results stimulated the study of the biopharmaceutical properties of some selected compounds, which were found to be characterized by a permeability from medium to high. Remarkably, the least permeable 7c showed both permeability and oral bioavailability (80%) higher than losartan, but its terminal half-life was shorter. These results suggest that the permeability is not a limiting factor in the pharmacokinetics of these AT 1 receptor antagonists.

Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages.

The enzyme Zmp1 is a zinc-containing peptidase that plays a critical role in the pathogenicity of Mycobacterium tuberculosis. Herein we describe the identification of a small set of Zmp1 inhibitors based on a novel 8-hydroxyquinoline-2-hydroxamate scaffold. Among the synthesized compounds, N-(benzyloxy)-8-hydroxyquinoline-2-carboxamide (1 c) was found to be the most potent Zmp1 inhibitor known to date, and its binding mode was analyzed both by kinetics studies and molecular modeling, identifying critical interactions of 1 c with the zinc ion and residues in the active site. The effect of 1 c on intracellular Mycobacterium survival was assayed in J774 murine macrophages infected with M. tuberculosis H37Rv or M. bovis BCG and human monocyte-derived macrophages infected with M. tuberculosis H37Rv. Cytotoxicity and genotoxicity were also assessed. Overall, inhibitor 1 c displays interesting in vitro antitubercular properties worthy of further investigation.

Design, synthesis, and preliminary biological evaluation of pyrrolo[3,4-c]quinolin-1-one and oxoisoindoline derivatives as aggrecanase inhibitors.

A small set of aggrecanase inhibitors based on the pyrrolo[3,4-c]quinolin-1-one or oxoisoindoline frameworks bearing a 4-(benzyloxy)phenyl substituent and different zinc binding groups were rationally designed and evaluated in silico by docking studies using the crystal structure of the ADAMTS-5 catalytic domain (PDB code: 3B8Z). The designed compounds were synthesized via straightforward routes and tested for their potential inhibitory activity against ADAMTS-5 and ADAMTS-4. Among the compounds containing the pyrrolo[3,4-c]quinolinone tricyclic system, hydroxamate derivative 2 b inhibited both ADAMTS-5 and ADAMTS-4, with IC(50) values in the submicromolar range and an inhibitory profile very similar to that of reference carboxylate derivative 11. Conversely, the corresponding carboxylate derivative 2 a was significantly less active and unable to discriminate between ADAMTS-5 and -4. The structure-activity relationship analysis of pyrroloquinolinone derivatives 2 a-i suggests that the carboxylate or hydroxamate groups of compounds 2 a,b play a key role in the interaction of these compounds with ADAMTS-5 and -4. On the other hand, the oxoisoindoline derivatives 3 a,b lack significant ADAMTS-4 inhibitory activity and inhibit ADAMTS-5 showing IC(25) values in the micromolar range.