Hughes Jr. F.M.,Medical University of South Carolina |
Hughes Jr. F.M.,Argolyn Bioscience Inc. |
Hughes Jr. F.M.,Halimed Pharmaceuticals, Inc. |
Shaner B.E.,Medical University of South Carolina |
And 5 more authors.
Open Medicinal Chemistry Journal | Year: 2013
Kappa-opioid agonists are particularly efficacious in the treatment of peripheral pain but suffer from central nervous system (CNS)-mediated effects that limit their development. One promising kappa-agonist is the peptidic compound CR665. Although not orally available, CR665 given i.v. exhibits high peripheral to CNS selectivity and benefits patients with visceral and neuropathic pain. In this study we have generated a series of derivatives of CR665 and screened them for oral activity in the acetic acid-induced rat writhing assay for peripheral pain. Five compounds were further screened for specificity of activation of kappa receptors as well as agonism and antagonism at mu and delta receptors, which can lead to off-target effects. All active derivatives engaged the kappa receptor with EC50s in the low nM range while agonist selectivity for kappa over mu or delta was >11,000-200,000-fold. No antagonist activity was detected. One compound was chosen for further analysis (Compound 9). An oral dose response of 9 in rats yielded an EC50 of 4.7 mg/kg, approaching a druggable level for an oral analgesic. To assess the peripheral selectivity of this compound an i.v. dose response in rats was assessed in the writhing assay and hotplate assay (an assay of CNS-mediated pain). The EC50 in the writhing assay was 0.032 mg/kg while no activity was detectable in the hotplate assay at doses as high as 30 mg/kg, indicating a peripheral selectivity of >900-fold. We propose that compound 9 is a candidate for development as an orally-available peripherally-restricted kappa agonist. © Hughes et al.
Lee J.H.,Emory University |
Wei L.,Emory University |
Gu X.,Emory University |
Wei Z.,Emory University |
And 3 more authors.
Journal of Neurotrauma | Year: 2014
Preclinical and clinical studies have shown therapeutic potential of mild-to-moderate hypothermia for treatments of stroke and traumatic brain injury (TBI). Physical cooling in humans, however, is usually slow, cumbersome, and necessitates sedation that prevents early application in clinical settings and causes several side effects. Our recent study showed that pharmacologically induced hypothermia (PIH) using a novel neurotensin receptor 1 (NTR1) agonist, HPI-201 (also known as ABS-201), is efficient and effective in inducing therapeutic hypothermia and protecting the brain from ischemic and hemorrhagic stroke in mice. The present investigation tested another second-generation NTR1 agonist, HPI-363, for its hypothermic and protective effect against TBI. Adult male mice were subjected to controlled cortical impact (CCI) (velocity=3 m/sec, depth=1.0 mm, contact time=150 msec) to the exposed cortex. Intraperitoneal administration of HPI-363 (0.3 mg/kg) reduced body temperature by 3-5°C within 30-60 min without triggering a shivering defensive reaction. An additional two injections sustained the hypothermic effect in conscious mice for up to 6 h. This PIH treatment was initiated 15, 60, or 120 min after the onset of TBI, and significantly reduced the contusion volume measured 3 days after TBI. HPI-363 attenuated caspase-3 activation, Bax expression, and TUNEL-positive cells in the pericontusion region. In blood-brain barrier assessments, HPI-363 ameliorated extravasation of Evans blue dye and immunoglobulin G, attenuated the MMP-9 expression, and decreased the number of microglia cells in the post-TBI brain. HPI-363 decreased the mRNA expression of tumor necrosis factor-α and interleukin-1β (IL-1β), but increased IL-6 and IL-10 levels. Compared with TBI control mice, HPI-363 treatments improved sensorimotor functional recovery after TBI. These findings suggest that the second generation NTR-1 agonists, such as HPI-363, are efficient hypothermic-inducing compounds that have a strong potential in the management of TBI. © 2014, Mary Ann Liebert, Inc.
Ghatnekar G.S.,FirstString Research, Inc. |
Ghatnekar G.S.,Halimed Pharmaceuticals, Inc. |
Ghatnekar G.S.,Regranion LLC |
Elstrom T.A.,FirstString Research, Inc. |
Elstrom T.A.,Regranion LLC
Methods in Molecular Biology | Year: 2013
This chapter will outline strategies and ideas for the commercialization a promising wound healing technology discovered in an academic setting. This would include, but not limited to addressing topics such as intellectual property protection, funding, technology development, and regulatory aspects (i.e., navigating through the FDA). © 2013 Springer Science+Business Media New York.
Choi K.-E.,Emory University |
Hall C.L.,Emory University |
Sun J.-M.,Emory University |
Wei L.,Emory University |
And 5 more authors.
FASEB Journal | Year: 2012
Compelling evidence from preclinical and clinical studies has shown that mild to moderate hypothermia is neuroprotective against ischemic stroke. Clinical applications of hypothermia therapy, however, have been hindered by current methods of physical cooling, which is generally inefficient and impractical in clinical situations. In this report, we demonstrate the potential of pharmacologically induced hypothermia (PIH) by the novel neurotensin receptor 1 (NTR1) agonist ABS-201 in a focal ischemic model of adult mice. ABS-201 (1.5-2.5 mg/kg, i.p.) reduces body and brain temperature by 2-5° C in 15-30 min in a dose-dependent manner without causing shivering or altering physiological parameters. Infarct volumes at 24 h after stroke are reduced by ~30-40% when PIH therapy is initiated either immediately after stroke induction or after 30-60 min delay. ABS-201 treatment increases bcl-2 expression, decreases caspase-3 activation, and TUNEL-positive cells in the peri-infarct region, and suppresses autophagic cell death compared to stroke controls. The PIH therapy using ABS-201 improves recovery of sensorimotor function as tested 21 d after stroke. These results suggest that PIH induced by neurotensin analogs represented by ABS-201 are promising candidates for treatment of ischemic stroke and possibly for other ischemic or traumatic injuries. © FASEB.
Halimed Pharmaceuticals, Inc. | Date: 2013-06-29
Embodiments described herein are directed to methods for the treatment and control of hyperlipidemia, hypercholesterolemia, dyslipidemia, and other lipid disorders, and in delaying the onset of or reducing the risk of conditions and sequelae that are associated with these diseases, including atherosclerosis and non-insulin dependent diabetes. In addition, embodiments are directed to methods of treating coronary heart disease and metabolic syndrome. Embodiments are also directed to neurotensin analogs. In embodiments, the neurotensin analogs may be capable of binding to neurotensin receptors and, upon binding, may modulate the levels of lipids in subjects.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 224.89K | Year: 2014
DESCRIPTION (provided by applicant): Treatment of peripheral pain of various origins remains a major unmet medical need, affecting tens to hundreds of millions of people nationwide at some time during their lives. Kappa-opioid agonists have been shown in peripheral pain models to be particularly efficacious but suffer from centrally mediated effects that have limited their development. Perhaps the most promising kappa-agonists under development are derivatives of the tetrapeptide D-Phe-D-Phe-D-Nle-D-Arg-NH2such as CR665, which exhibits high (but not absolute) peripheral to central (CNS) selectivity when administered IV. Clinical studies have shown significant benefit in patients with visceral and neuropathic pain; however, the compound is not active when administered orally which significantly limits its potential use as an analgesic for peripheral pain. As proof of concept, application of the Halimed Pharmaceuticals non- natural amino acid technology to CR665 produced derivatives that exhibit oral acti
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 883.73K | Year: 2011
DESCRIPTION (provided by applicant): Stroke is the third leading cause of death in the United States. In spite of intensive investigations, clinical therapies for treating acute stroke patients remain limited and unsatisfactory. There are consistent animal and human data that mild to moderate hypothermia (reducing body temperature to 32-34oC) is generally safe and improves outcome after brain ischemia even when initiated hours after ischemia occurs. Different from most neuroprotective drugs that usuallytarget only one mechanism, hypothermia therapy has the advantage of global protection on all cell types and tissues in both gray and white matters. Several important limitations, however, have precluded the widespread use of hypothermia therapy in strokepatients. The major obstruction is that existing forced cooling techniques are ineffectual and/or impractical in clinical settings. To overcome the shortcomings of current methods, the concept of regulated hypothermia induced by pharmacological means has been proposed as a new strategy in hypothermia therapy; although there have been no drugs that can be used for regulated hypothermia therapy. To this end, we have synthesized and tested novel neurotensin(NT)[8-13] derivatives, such as ABS201 and ABS601,that are potent hypothermic compounds and have dramatic neuroprotective activity in animal stroke models. These NT compounds show no toxic effects, attenuate infarct formation by nearly 50% even when administered 45 min after the onset of ischemia. The mechanism of protection appears to involve their ability to cross the blood brain barrier, bind to the NT receptor as agonists, and reduce the set point of the central temperature control so that systemic hypothermia in the absence of shivering is promoted. It is thus hypothesized that NT/ABS derivatives have strong potential of being developed for regulated hypothermia therapy. In the Phase I study, we will compare the hypothermic potency of six NT/ABS derivatives. Two leading compounds without detectableside effects will be tested and compared for their neuroprotection in aged rats of two stroke models of transient and permanent ischemia. This translational investigation is not intended to delineate the mechanism of hypothermia protection, which has beenextensively studied so far. Rather, we aim to demonstrate the feasibility of the chemical-induced hypothermia therapy and move to more systematic preclinical examinations of a Phase II investigation. Our ultimate goal is to advance the drug-induced hypothermia therapy to the clinic. PUBLIC HEALTH RELEVANCE: Ischemic stroke is the third leading cause of human death and disability in the US. This investigation will develop a chemical-induced hypothermia therapy for stroke patients. The comprehensive neuroprotective effects of clinically feasible hypothermia therapy will be studied in two different stroke models, which will facilitate the translation of the therapy to clinical applications.