Drug-Like Property Profiling of Novel Neuroprotective Compounds to Treat Acute Ischemic Stroke: Guidelines to Develop Pleiotropic Molecules.

Drug-Like Property Profiling of Novel Neuroprotective Compounds to Treat Acute Ischemic Stroke: Guidelines to Develop Pleiotropic Molecules.

Transl Stroke Res. 2013 Jun 1; 4(3): 328-342
Lapchak PA

The development of novel neuroprotective compounds to treat acute ischemic stroke (AIS) has been problematic and quite complicated, since many candidates that have been tested clinically lacked significant pleiotropic activity, were unable to effectively cross the blood brain barrier (BBB), had poor bioavailability or were toxic. Moreover, the compounds did not confer significant neuroprotection or clinical efficacy measured using standard behavioral endpoints, when studied in clinical trials in a heterogeneous population of stroke patients. To circumvent some of the drug development problems describe above, we have used a rational funnel approach to identify and develop promising candidates. Using a step-wise approach, we have identified a series of compounds based upon two different neuroprotection assays. We have then taken the candidates and determined their “drug-like” properties. This guidelines article details in vitro screening assays used to show pleiotropic activity of a series of novel compounds; including enhanced neuroprotective activity compared to the parent compound fisetin. Moreover, for preliminary drug de-risking or risk reduction during development, we used compound assessment in the CeeTox assay, ADME toxicity using the AMES test for genotoxicity and interaction with Cytochrome P450 using CYP450 inhibition analysis against a spectrum of CYP450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) as a measure of drug interaction. Moreover, the compounds have been studied using a transfected Madin Darby canine kidney (MDCK) cell assay to assess blood brain barrier penetration (BBB). Using this series of assays, we have identified 4 novel molecules to be developed as an AIS treatment. HubMed – drug


Renoprotection and the Bardoxolone Methyl Story – Is This the Right Way Forward? A Novel View of Renoprotection in CKD Trials: A New Classification Scheme for Renoprotective Agents.

Nephron Extra. 2013 1; 3(1): 36-49
Onuigbo M

In the June 2011 issue of the New England Journal of Medicine, the BEAM (Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes) trial investigators rekindled new interest and also some controversy regarding the concept of renoprotection and the role of renoprotective agents, when they reported significant increases in the mean estimated glomerular filtration rate (eGFR) in diabetic chronic kidney disease (CKD) patients with an eGFR of 20-45 ml/min/1.73 m(2) of body surface area at enrollment who received the trial drug bardoxolone methyl versus placebo. Unfortunately, subsequent phase IIIb trials failed to show that the drug is a safe alternative renoprotective agent. Current renoprotection paradigms depend wholly and entirely on angiotensin blockade; however, these agents [angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)] have proved to be imperfect renoprotective agents. In this review, we examine the mechanistic limitations of the various previous randomized controlled trials on CKD renoprotection, including the paucity of veritable, elaborate and systematic assessment methods for the documentation and reporting of individual patient-level, drug-related adverse events. We review the evidence base for the presence of putative, multiple independent and unrelated pathogenetic mechanisms that drive (diabetic and non-diabetic) CKD progression. Furthermore, we examine the validity, or lack thereof, of the hyped notion that the blockade of a single molecule (angiotensin II), which can only antagonize the angiotensin cascade, would veritably successfully, consistently and unfailingly deliver adequate and qualitative renoprotection results in (diabetic and non-diabetic) CKD patients. We clearly posit that there is this overarching impetus to arrive at the inference that multiple, disparately diverse and independent pathways, including any veritable combination of the mechanisms that we examine in this review, and many more others yet to be identified, do concurrently and asymmetrically contribute to CKD initiation and propagation to end-stage renal disease (ESRD) in our CKD patients. We conclude that current knowledge of CKD initiation and progression to ESRD, the natural history of CKD and the impacts of acute kidney injury on this continuum remain in their infancy and call for more research. Finally, we suggest a new classification scheme for renoprotective agents: (1) the single-pathway blockers that block a single putative pathogenetic pathway involved in CKD progression, as typified by ACE inhibitors and/or ARBs, and (2) the multiple-pathway blockers that are able to block or antagonize the effects of multiple pathogenetic pathways through their ability to simultaneously block, downstream, the effects of several pathways or mechanisms of CKD to ESRD progression and could therefore concurrently interfere with several unrelated upstream pathways or mechanisms. We surmise that maybe the ideal and truly renoprotective agent, clearly a multiple-pathway blocker, is on the horizon. This calls for more research efforts from all. HubMed – drug


Effect on Prediction when Modeling Covariates in Bayesian Nonparametric Models.

J Stat Theory Pract. 2013 Apr 1; 7(2): 204-218
Cruz-Marcelo A, Rosner GL, Müller P, Stewart CF

In biomedical research, it is often of interest to characterize biologic processes giving rise to observations and to make predictions of future observations. Bayesian nonparametric methods provide a means for carrying out Bayesian inference making as few assumptions about restrictive parametric models as possible. There are several proposals in the literature for extending Bayesian nonparametric models to include dependence on covariates. Limited attention, however, has been directed to the following two aspects. In this article, we examine the effect on fitting and predictive performance of incorporating covariates in a class of Bayesian nonparametric models by one of two primary ways: either in the weights or in the locations of a discrete random probability measure. We show that different strategies for incorporating continuous covariates in Bayesian nonparametric models can result in big differences when used for prediction, even though they lead to otherwise similar posterior inferences. When one needs the predictive density, as in optimal design, and this density is a mixture, it is better to make the weights depend on the covariates. We demonstrate these points via a simulated data example and in an application in which one wants to determine the optimal dose of an anticancer drug used in pediatric oncology. HubMed – drug


Towards the Total Synthesis of Pl-3: Preparation of the Eastern Fragment through a Diastereoselective SmI2-Mediated Reformatsky Reaction.

European J Org Chem. 2013 Apr; 2013(12): 2293-2297
Fürst R, Lentsch C, Rinner U

The jatrophane diterpene Pl-3, isolated in 2003 from Euphorbia platyphyllos, is a structurally complex natural product with highly promising biological properties that include pronounced antiproliferative activity and the inhibition of the efflux-pump activity of multidrug resistance p-glycoprotein. Herein, the synthesis of the eastern fragment of Pl-3 is outlined. The target compound is synthesized in nine synthetic operations in good overall yield, starting from readily available d-ribose. The key step in the preparation of the eastern part of Pl-3 is a diastereoselective SmI2-mediated Reformatsky reaction. The proposed route is highly flexible and could also be applied to the synthesis of structurally related jatrophane diterpenes. HubMed – drug