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Principal Investigator: Zsuzsanna Kinga Zsengeller
Organization: BETH ISRAEL DEACONESS MEDICAL CENTER
Fiscal Year: 2024
Award: $262,808
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
PROJECT SUMMARY: Our lab in collaboration with Akkadian Therapeutics, Inc. (AKTX), have demonstrated
the beneficial effects of the novel catalytic radical scavenger and nitric oxide donor/vasodilator, AKT-1005, in
established in vitro and in vivo models of preeclampsia. However, the development of AKT-1005 itself as a drug
candidate is limited by poor water solubility, instability and sub-optimal pharmacokinetic (PK)
characteristics. To circumvent these issues, we proposes to synthesize, screen and test water-soluble prodrugs
of AKT-1005 for solubility, stability, and release of AKT-1005 in vitro and in vivo, in order to select candidates
for in vivo efficacy studies using an established rodent model of preeclampsia.
Preeclampsia (PE) is a serious life-threatening complication during pregnancy, characterized by high
maternal blood pressure, kidney dysfunction, proteinuria, and in severe cases, eclampsia and premature birth.
It affects around 5% of pregnancies. While the etiology and pathogenesis of PE are elusive, placental ischemia/
hypoxia due to impaired placental development and subsequent release of anti-angiogenic factors (sFlt1 and
sEng) are key components There is also compelling evidence for the involvement of oxidative stress,
and concurrent mitochondrial alterations in PE.
AKT-1005, is a novel cell-permeable redox-active agent incorporating two chemical active moieties: 1) an
organic nitrate that releases nitric oxide in vivo, and 2) a pyrrolidine nitroxide that acts as a degradation catalyst
of reactive oxygen species (ROS). We propose that these dual actions of AKT-1005 will (i) efficiently remove ROS
responsible for the deleterious effects of oxidative stress in PE, (ii) reduce maternal blood pressure by the direct
vasodilator effect of NO on blood vessel walls, and (iii) increase the bioavailability of NO, which is deficient in
PE, but not other deleterious reactive nitrogen species (RNS, a side-reaction of NO with ROS).
For selected prodrugs, systemic PK of parent prodrug, AKT-1005 and the major metabolite, HMP, will be
determined in rodents following IV and IP dosing to the efficacy species (mouse) at doses found efficacious for
AKT-1005 in previous studies. Cross-species metabolic comparisons for preferred prodrug(s) using isolated liver
microsomes from mouse, rat, dog or human will also be performed.
Selected prodrugs with the best attributes from the above will then be compared to AKT-1005 in an
established/published murine model of PE. Time-pregnant mice will be subjected to adenovirus-sFLT1
(AdsFLT1), which reliably induces the main features of PE, and treated with prodrug or vehicle control 3 days
later. Mice will be evaluated for blood pressure, renal function, histologic damage, 3-nitrotyrosine (3-NT) tissue
immunoreactivity, plasma biomarkers (oxidative/nitrosative stress, sFlt-1 and VEGF, and pregnancy outcomes,
etc.) The proposed studies will provide a rational foundation for advancement of an AKT-1005 prodrug,
through lead optimization, to clinical candidate as a first-line early intervention in high-risk PE pregnancies.
Terms: <1(2H)-Phthalazinone, hydrazone><3-mononitrotyrosine><3-nitrotyrosine><AKT><Active Oxygen><Address><Adenoviridae><Adenoviruses><Affect><Akt protein><Angiogenesis Antagonists><Angiogenesis Blockers><Angiogenesis Factor><Angiogenesis Inhibitors><Angiogenetic Antagonists><Angiogenetic Inhibitors><Angiogenic Antagonists><Angiogenic Factor><Angiogenic Inhibitors><Angiostatic Agents><Anti-Angiogenetic Agents><Anti-Angiogenic Agents><Anti-Angiogenic Drugs><Antiangiogenesis Agents><Antiangiogenic Agents><Antiangiogenic Drugs><Antioxidants><Apresoline><Apressin><Bioavailability><Biological><Biological Availability><Biological Markers><Blood Plasma><Blood Pressure><Blood Vessels><Body Tissues><Brain Hypoxia-Ischemia><Canine Species><Canis familiaris><Causality><Cell Body><Cells><Cells Placenta-Tissue><Chemicals><Clinical><Collaborations><Common Rat Strains><Complication><Development><Disease><Disorder><Dogs><Dogs Mammals><Dose><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drug Precursors><Dysfunction><EPH Gestosis><Early Intervention><Eclampsia><Endogenous Nitrate Vasodilator><Endothelium-Derived Nitric Oxide><Environment><Esters><Etiology><Exhibits><Female><Foundations><Free Radicals><Functional disorder><Gestation><Half-Life><Histologic><Histologically><Human><Hydralazine><Hydrazinophthalazine><Hydrogen Oxide><Hydrolysis><Hypertension><Impairment><In Vitro><Incubated><Intermediary Metabolism><Kidney><Kidney Urinary System><LC/MS><Life><Liver Microsomes><Measurement><Metabolic><Metabolic Processes><Metabolism><Methods><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Mononitrogen Monoxide><Murine><Mus><NO3-><Neovascularization Inhibitors><Nitrates><Nitric Oxide><Nitric Oxide Donors><Nitrogen><Nitrogen Monoxide><Nitrogen Protoxide><Normal Placentoma><O element><O2 element><Oxidation-Reduction><Oxidative Stress><Oxygen><Oxygen Radicals><Parents><Pathogenesis><Pathway interactions><Perinatal Mortalities><Perinatal lethality><Perinatal mortality demographics><Permeability><Peroxonitrite><Pharmacokinetics><Physiologic Availability><Physiopathology><Placenta><Placenta Embryonic Tissue><Placental Development><Placentation><Placentome><Plasma><Plasma Serum><Pre-Eclampsia><Preeclampsia><Pregnancy><Pregnancy Complications><Pregnancy Outcome><Pregnancy Toxemias><Premature Birth><Prematurely delivering><Preterm Birth><Prevention><Pro-Drugs><Pro-Oxidants><Prodrugs><Protein Kinase B><Proteinuria><Proteinuria-Edema-Hypertension Gestosis><Proto-Oncogene Proteins c-akt><Publishing><Pyrrolidines><RAC-PK protein><Rat><Rats Mammals><Rattus><Reaction><Reactive Nitrogen Species><Reactive Oxygen Species><Redox><Renal Tissue><Renal function><Reticuloendothelial System, Serum, Plasma><Rodent><Rodent Model><Rodentia><Rodents Mammals><Series><Side><Solubility><Structure><Superoxide Anion><Superoxide Radical><Superoxides><Symptoms><Testing><Therapeutic><Time><Tissues><Up-Regulation><Upregulation><VEGF><VEGFs><Vascular Endothelial Growth Factors><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vasodilating Agent><Vasodilator Agents><Vasodilator Drugs><Vasodilators><Water><antiangiogenic><bio-markers><biologic><biologic marker><biomarker><blood pressure medication><blood pressure medicine><c-akt protein><candidate selection><canine><catalyst><causation><clinical candidate><complications during pregnancy><design><designing><developmental><disease causation><domestic dog><drug candidate><efficacy study><endothelial cell derived relaxing factor><functional group><high blood pressure><high risk><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><hypoxia/ischemia><immunoreactivity><improved><in vivo><in vivo Model><inflammation marker><inflammatory marker><innovate><innovation><innovative><kidney dysfunction><kidney function><lead optimization><liquid chromatography mass spectrometry><maternal hypertension><maternal morbidity><mitochondrial><mouse model><murine model><nitrate><nitrosative stress><nitrotyrosine><novel><oxidant stress><oxidation reduction reaction><parent><pathophysiology><pathophysiology of pre-eclampsia><pathophysiology of preeclampsia><pathway><perinatal deaths><perinatal morbidity><peroxynitrite><pharmacokinetic characteristic><physical property><pre-eclamptic><pregnancy toxemia/hypertension><pregnancy-related complications><pregnant><premature><premature childbirth><premature delivery><prematurity><preterm delivery><proto-oncogene protein RAC><proto-oncogene protein akt><rac protein kinase><related to A and C-protein><renal><renal dysfunction><restoration><uptake><vascular><water monitoring><water quality monitoring><water solubility><water testing>