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WAUWATOSA, WI, United States

Williams J.M.,University of Mississippi Medical Center | Zhang J.,University of Mississippi Medical Center | North P.,Medical College of Wisconsin | Lacy S.,Exelixis | And 3 more authors.
American Journal of Physiology - Renal Physiology

This study examined the effects of two new selective metalloprotease (MMP) inhibitors, XL081 and XL784, on the development of renal injury in rat models of hypertension, Dahl salt-sensitive (Dahl S) and type 2 diabetic nephropathy (T2DN). Protein excretion rose from 20 to 120 mg/day in Dahl S rats fed a high-salt diet (8.0% NaCl) for 4 wk to induce hypertension. Chronic treatment with XL081 markedly reduced proteinuria and glomerulosclerosis, but it also attenuated the development of hypertension. To determine whether an MMP inhibitor could oppose the progression of renal damage in the absence of changes in blood pressure, Dahl S rats were fed a high-salt diet (4.0% NaCl) for 5 wks to induce renal injury and then were treated with the more potent and bioavailable MMP inhibitor XL784 either given alone or in combination with lisinopril and losartan. Treatment with XL784 or the ANG II blockers reduced proteinuria and glomerulosclerosis by ~30% and had no effect on blood pressure. Proteinuria fell from 150 to 30 mg/day in the rats receiving both XL784 and the ANG II blockers, and the degree of renal injury fell to levels seen in normotensive Dahl S rats maintained from birth on a low-salt diet. In other studies, albumin excretion rose from 125 to >200 mg/day over a 4-mo period in 12-mo-old uninephrectomized T2DN rats. In contrast, albumin excretion fell by >50% in T2DN rats treated with XL784, lisinopril, or combined therapy. XL784 reduced the degree of glomerulosclerosis in the T2DN rats to a greater extent than lisinopril, and combined therapy was more effective than either drug alone. These results indicate that chronic administration of a selective MMP inhibitor delays the progression, and may even reverse hypertension and diabetic nephropathy © 2011 the American Physiological Society. Source

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 343.80K | Year: 2010

DESCRIPTION (provided by applicant): The number of patients in the United States afflicted with learning and memory disorders is rapidly increasing. This necessitates the development of new, better acting and safer medications for enhancing cognition. In this SBIR Phase I project, PhysioGenix will determine the efficacy, pharmacokinetics (PK), maximum tolerated dose and potential side-effects of PWZ-029, a benzodiazepine (BZ) compound that may prove useful for treating patients with learning and memory disorders. BZs are listed as a Core Medicine in the WHO Essential Drug List and those on the market, such as Valium and Xanax, are widely used for the treatment of anxiety, panic attacks, insomnia, agitation and seizures. BZs can cause depressing (agonist) or stimulating (inverse agonist) effects on the central nervous system by modulating the GABAA receptor, the most prevalent inhibitory receptor within the brain. However, side-effects are common in patients treated with BZs and this can limit their use. For example, Valium is a full agonist of the GABAA receptor but has a side-effect profile in patients that includes sedation, amnesia and ataxia. Nonselective BZ inverse agonists, like DMCM, are often anxiogenic and can cause seizures in animals. Because these unwanted side-effects can be attributed to nonspecific interactions of the BZs for different subunits of the GABAA receptor complex, functionally specific BZs that retain only the desired pharmacological response are being developed. GABAA receptor complexes that contain 15 subunits are abundantly expressed in the hippocampus and therefore considered to be a therapeutic target for treating cognitive disorders, like Alzheimer's and ADHD. With this in mind, PWZ-029 was designed by Dr. James Cook of the University of Wisconsin-Milwaukee, to be an inverse agonist for the GABAA receptor having subtype and functional selectivity predominantly at the 15 subunit. Recent in vitro studies in oocytes have shown that PWZ-029 has up to 60-fold more functional selectivity for the 15 subunit compared to 11, 12 and 13. Behavior tests also suggest that PWZ-029 has cognition enhancing capabilities, thereby making it a feasible therapeutic candidate. Here, the ability of PWZ-029 to enhance cognition will be assessed in both rodents and rhesus monkeys. For rodent studies, the PK of PWZ-029 will be measured in blood and brain following oral administration to assess its bioavailability. Maximum tolerated dose studies will be carried out as part of lead optimization toxicology, which may also detect if PWZ-029 will cause seizures. The proconvulsant liability of PWZ-029 will be measured directly using the PTZ mouse model. The behavior tests will incorporate rat strains that have natural deficits in cognition along with a standard scopolamine amnesia model. Finally, rhesus monkey will be used to measure potential sedative side-effects along with confirming preliminary data for the ability of PWZ-02 to enhance cognition. Success will lead to Phase II studies that will aim to expand preclinical safety and efficacy testing ultimately leading to clinical trials. Commercialization opportunities will be realized via drug development efforts for treating mental health disorders. PUBLIC HEALTH RELEVANCE: Preclinical studies that determine the bioavailability and safety of functionally selective benzodiazepine compounds, like PWZ-029, are required prior to further drug development. Screening of compounds with relevant disease models will help to assess their therapeutic potential. Patients with learning disorders and those suffering from complications due to neurodegenerative diseases will greatly benefit as PWZ-029 moves another step closer to the clinic.

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 134.43K | Year: 2004

DESCRIPTION (provided by applicant): The concept of a pre-clinical, drug screen for genetic effects was developed by PhysioGenix in Phase I of this project. The screen consists of inbred rats bred in a combinatorial fashion such that F1 offspring mimi

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 498.61K | Year: 2004

DESCRIPTION (provided by applicant): This Phase I SBIR project uses a new Quality Control microarray (QCarray) technology to generate Drug Toxicity Signatures (DTSs) for predicting liver toxicity in rat. The QCarray enables each element on every array

Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 1.64M | Year: 2006

DESCRIPTION (provided by applicant): PhysioGenix plans to commercialize a rat discovery platform that markedly accelerates the deployment of genetic tools for drug development by Pharma. While genetics can offer pharmaceutical companies a powerful discovery tool, this strategy has not been widely adopted because traditional methods are too slow. The consomic rat panels are validated as a strategy for pharmaceutical researchers to discover new therapeutics targets and treatments for common human diseases, like hypertension and the associated cardiovascular and renal diseases, in a parallel fashion never before available to the industry. The consomic technology is a fast way (6-9 months) to go from mapping disease quantitative trait loci to identifying a handful of targets while enabling parallel functional studies in rats. No other genetic technology is close to this pace. The consomic technology we plan to commercialize is comprised of two complete rat panels each having 22 chromosomal substitution strains. Since the introgressed chromosomes come from a ?normal? strain superimposed upon a ?diseased? genome background, curing a disease phenotype provides a bioassay to screen for protective genes that can lead to the discovery of new therapeutic targets. To date, consomic rats have been successfully used in academia to identify chromosomes that cure salt-sensitive hypertension, global ischemia and end-stage renal disease. The goal of this Fast-Track application is to support PhysioGenix?s efforts to move the consomic rat panels from the academic sector into Pharma?s preclinical drug development programs. In Phase I studies, we will complete the transfer and re-derivation of one consomic panel (SS.BN) to our commercial breeder, mine the PhysGen database for clinically relevant phenotypes and characterize the progenitor strains (FHH, SS and BN) for neuropsychiatric disorders (e.g. immobility for depression and open-field activity monitoring for hyperactivity). We will also combine the PhysGen data into more usable datasets for our Pharma clients, as well as providing internal leads for PhysioGenix scientists. In Phase II, PhysioGenix will finish cleaning up the second consomic panel (FHH.BN), measure phenotypic traits for neuropsychiatric disorders in both consomic panels and extend the technology to new applications, like pharmacogenomics. In this latter case, we will perform testing with tacrine (a commonly used Alzheimer?s medication with hepatotoxic side effects) to validate the consomic rat panels as a tool to identify the genetic basis of drug efficacy and toxicity. As the era of genomics begins to impact medicine, we wonder how can progress be made without a reliable model system for pharmacogenetic testing? The consomic rat panels may represent the critical tool for the realization of personalized medicine.

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