Aminoalkoxycarbonyloxymethyl Ether Prodrugs with a pH-Triggered Release Mechanism: A Case Study Improving the Solubility, Bioavailability, and Efficacy of Antimalarial 4(1H)-Quinolones with Single Dose Cures.

Preclinical and clinical development of numerous small molecules is prevented by their poor aqueous solubility, limited absorption, and oral bioavailability. Herein, we disclose a general prodrug approach that converts promising lead compounds into aminoalkoxycarbonyloxymethyl (amino AOCOM) ether-substituted analogues that display significantly improved aqueous solubility and enhanced oral bioavailability, restoring key requirements typical for drug candidate profiles. The prodrug is completely independent of biotransformations and animal-independent because it becomes an active compound via a pH-triggered intramolecular cyclization-elimination reaction. As a proof-of-concept, the utility of this novel amino AOCOM ether prodrug approach was demonstrated on an antimalarial compound series representing a variety of antimalarial 4(1H)-quinolones, which entered and failed preclinical development over the last decade. With the amino AOCOM ether prodrug moiety, the 3-aryl-4(1H)-quinolone preclinical candidate was shown to provide single-dose cures in a rodent malaria model at an oral dose of 3 mg/kg, without the use of an advanced formulation technique.

Design and Synthesis of Orally Bioavailable Piperazine Substituted 4(1H)-Quinolones with Potent Antimalarial Activity: Structure-Activity and Structure-Property Relationship Studies.

Malaria deaths have been decreasing over the last 10-15 years, with global mortality rates having fallen by 47% since 2000. While the World Health Organization (WHO) recommends the use of artemisinin-based combination therapies (ACTs) to combat malaria, the emergence of artemisinin resistant strains underscores the need to develop new antimalarial drugs. Recent in vivo efficacy improvements of the historical antimalarial ICI 56,780 have been reported, however, with the poor solubility and rapid development of resistance, this compound requires further optimization. A series of piperazine-containing 4(1H)-quinolones with greatly enhanced solubility were developed utilizing structure-activity relationship (SAR) and structure-property relationship (SPR) studies. Furthermore, promising compounds were chosen for an in vivo scouting assay to narrow selection for testing in an in vivo Thompson test. Finally, two piperazine-containing 4(1H)-quinolones were curative in the conventional Thompson test and also displayed in vivo activity against the liver stages of the parasite.

Chronic inflammation and apoptosis propagate in ischemic cerebellum and heart of non-human primates.

The major pathological consequences of cerebral ischemia are characterized by neurological deficits commonly ascribed to the infarcted tissue and its surrounding region, however, brain areas, as well as peripheral organs, distal from the original injury may manifest as subtle disease sequelae that can increase the risks of co-morbidities complicating the disease symptoms. To evaluate the vulnerability of the cerebellum and the heart to secondary injuries in the late stage of transient global ischemia (TGI) model in non-human primates (NHP), brain and heart tissues were collected at six months post-TGI. Unbiased stereological analyses of immunostained tissues showed significant Purkinje cells loss in lobule III and lobule IX of the TGI cerebellum relative to sham cerebellum, with corresponding upregulation of inflammatory and apoptotic cells. Similarly, TGI hearts revealed significant activation of inflammatory and apoptotic cells relative to sham hearts. Aberrant inflammation and apoptosis in the cerebellum and the heart of chronic TGI-exposed NHPs suggest distal secondary injuries manifesting both centrally and peripherally. These results advance our understanding on the sustained propagation of chronic secondary injuries after TGI, highlighting the need to develop therapeutic interventions targeting the brain, as well as the heart, in order to abrogate cerebral ischemia and its related co-morbidities.

Contemplating stem cell therapy for epilepsy-induced neuropsychiatric symptoms.

Epilepsy is a debilitating disease that impacts millions of people worldwide. While unprovoked seizures characterize its cardinal symptom, an important aspect of epilepsy that remains to be addressed is the neuropsychiatric component. It has been documented for millennia in paintings and literature that those with epilepsy can suffer from bouts of aggression, depression, and other psychiatric ailments. Current treatments for epilepsy include the use of antiepileptic drugs and surgical resection. Antiepileptic drugs reduce the overall firing of the brain to mitigate the rate of seizure occurrence. Surgery aims to remove a portion of the brain that is suspected to be the source of aberrant firing that leads to seizures. Both options treat the seizure-generating neurological aspect of epilepsy, but fail to directly address the neuropsychiatric components. A promising new treatment for epilepsy is the use of stem cells to treat both the biological and psychiatric components. Stem cell therapy has been shown efficacious in treating experimental models of neurological disorders, including Parkinson's disease, and neuropsychiatric diseases, such as depression. Additional research is necessary to see if stem cells can treat both neurological and neuropsychiatric aspects of epilepsy. Currently, there is no animal model that recapitulates all the clinical hallmarks of epilepsy. This could be due to difficulty in characterizing the neuropsychiatric component of the disease. In advancing stem cell therapy for treating epilepsy, experimental testing of the safety and efficacy of allogeneic and autologous transplantation will require the optimization of cell dosage, delivery, and timing of transplantation in a clinically relevant model of epilepsy with both neurological and neuropsychiatric symptoms of the disease as the primary outcome measures.

Utilizing pharmacotherapy and mesenchymal stem cell therapy to reduce inflammation following traumatic brain injury.

The pathologic process of chronic phase traumatic brain injury is associated with spreading inflammation, cell death, and neural dysfunction. It is thought that sequestration of inflammatory mediators can facilitate recovery and promote an environment that fosters cellular regeneration. Studies have targeted post-traumatic brain injury inflammation with the use of pharmacotherapy and cell therapy. These therapeutic options are aimed at reducing the edematous and neurodegenerative inflammation that have been associated with compromising the integrity of the blood-brain barrier. Although studies have yielded positive results from anti-inflammatory pharmacotherapy and cell therapy individually, emerging research has begun to target inflammation using combination therapy. The joint use of anti-inflammatory drugs alongside stem cell transplantation may provide better clinical outcomes for traumatic brain injury patients. Despite the promising results in this field of research, it is important to note that most of the studies mentioned in this review have completed their studies using animal models. Translation of this research into a clinical setting will require additional laboratory experiments and larger preclinical trials.

Growth factor therapy sequesters inflammation in affording neuroprotection in cerebrovascular diseases.

INTRODUCTION: In recent years, accumulating evidence has demonstrated the key role of inflammation in the progression of cerebrovascular diseases. Inflammation can persist over prolonged period of time after the initial insult providing a wider therapeutic window. Despite the acute endogenous upregulation of many growth factors after the injury, it is not sufficient to protect against inflammation and to regenerate the brain. Therapeutic approaches targeting both dampening inflammation and enhancing growth factors are likely to provide beneficial outcomes in cerebrovascular disease. AREAS COVERED: In this mini review, we discuss major growth factors and their beneficial properties to combat the inflammation in cerebrovascular diseases. Emerging biotechnologies which facilitate the therapeutic effects of growth factors are also presented in an effort to provide insights into the future combination therapies incorporating both central and peripheral abrogation of inflammation. Expert commentary: Many studies discussed in this review have demonstrated the therapeutic effects of growth factors in treating cerebrovascular diseases. It is unlikely that one growth factor can be used to treat these complex diseases. Combination of growth factors and anti-inflammatory modulators may clinically improve outcomes for patients. In particular, transplantation of stem cells may be able to achieve both goals of modulating inflammation and upregulating growth factors. Large preclinical studies and multiple laboratory collaborations are needed to advance these findings from bench to bedside.