SBIR-STTR Award

More than 850,000 myocardial infarctions (MI) occur in the US annually, 300,000 of which are recurrences, carrying with them a two-fold increased risk of death. Recurrent MI take place owing to the high rates of reocclusion of cardiac arteries observed following initially successful fibrinolytic therapy with t-PA or streptokinase. Plasmin-induced activation of the intrinsic coagulation system, proceeding via two tightly- linked enzymes, factor XII (FXII) and plasma kallikrein (PK), may be the mechanism for generation of new thrombin during fibrinolysis. Mice deficient in FXII are highly resistant to the formation of occluding arterial thrombi in multiple models of injury-mediated arterial thrombus formation. The extent of PK activation regulates the amount of FXII activity, and thus inhibition of PK would provide a novel anti-thrombotic therapeutic approach for the treatment of acute MI, especially as adjunctive therapy to current standard-of- care fibrinolytic treatments. We have generated novel small molecule PK inhibitors displaying both high potency for PK inhibition and selectivity against other enzymes in the intrinsic pathways. In addition, sensitive plasma-based assays have been developed to quantitatively measure the extent of inhibition of the intrinsic coagulation pathway resulting from PK inhibition. Using these assays, we have demonstrated that inhibition of PK is more effective than depletion of FXII for inhibiting thrombin generation and coagulation by the intrinsic pathway. We propose in Phase I to develop PK inhibitors that have defined potency, selectivity and pharmacokinetic properties, then test the best compounds in a mouse model of arterial thrombosis, so as to provide proof-of-concept that selective inhibition of PK could provide a novel therapeutic approach for reducing risk of reocclusion and reinfarction following fibrinolytic therapy for MI. The successful completion of Phase I will also result in the identification of one or more lead compounds suitable for preclinical development in Phase II for adjunctive therapy for MI patients undergoing fibrinolytic therapy. This project proposes that inhibition of the intrinsic coagulation pathway, to be accomplished by inhibition of a key enzyme of this pathway, plasma kallikrein (PK), would have significant therapeutic impact in reducing the risk of reocclusion and reinfarction in patients with mycorcardial infarction (MI) who have undergone fibrinolytic treatment. It seeks to optimize prototype novel small molecule inhibitors of PK to obtain lead molecules that will be tested in animal models of thrombosis in Phase I, then proceed into preclinical development in Phase II for adjunctive therapy for MI patients receiving fibrinolytic therapy.

Thesaurus Terms:
fibrin, inhibitor /antagonist, kallikrein, myocardial infarction, protein structure function, small molecule, therapy design /development analog, combination therapy, peptide chemical synthesis, pharmacokinetics, plasma, thrombosis bioengineering /biomedical engineering, blood test, laboratory mouse, laboratory rat

There nearly 24 million people in the U.S. who suffer from diabetes and who are at risk for diabetic retinopathy (DR), a vascular complication of diabetes that is the leading cause of blindness in working age adults. A major cause of vision loss in DR is increased retinal vascular permeability (RVP), leading to a build-up of fluid in the macula, a debilitating clinical condition known as diabetic macular edema (DME). We show by multiple lines of evidence that the serine protease plasma kallikrein (PK) is involved in the increased RVP in animal models of diabetes and hypertension. When delivered subcutaneously, PK inhibitors developed as part of our phase 1 grant effectively inhibit RVP in animal models of hypertension. PK inhibitors with oral bioavailability, however, would be preferred for chronic and long term administration to diabetics. The goal of this phase II grant is to develop a safe, effective and orally-available PK inhibitor for the chronic, long term treatment of DME in DR. We will specifically focus on our current series of PK inhibitors that have promise for oral bioavailability and are amenable to chemical changes that are proven to increase oral bioavailability. The inhibitors will be tested for their ability to block RVP in hypertensive and diabetic animals when given orally at moderate daily doses. The safety and potential "off-target" effects of the efficacious compounds will subsequently be determined so as to identify an orally-available compound with a sufficient safety margin that can be considered for further preclinical development and IND-enabling toxicology studies.

Public Health Relevance:
This Phase II project proposes that inhibition of the serine protease plasma kallikrein (PK), would have significant therapeutic impact in reducing diabetic macular edema (DME) in diabetic retinopathy (DR). It seeks to optimize a lead series of small molecule inhibitors of PK to obtain orally available lead molecules for testing in animal models of diabetes- and hypertension-induced retinal vascular permeability, followed by initial evaluation of the potential safety margin for the lead molecule in a repeat-dose acute toxicology study.

Public Health Relevance Statement:
Narrative This Phase II project proposes that inhibition of the serine protease plasma kallikrein (PK), would have significant therapeutic impact in reducing diabetic macular edema (DME) in diabetic retinopathy (DR). It seeks to optimize a lead series of small molecule inhibitors of PK to obtain orally available lead molecules for testing in animal models of diabetes- and hypertension-induced retinal vascular permeability, followed by initial evaluation of the potential safety margin for the lead molecule in a repeat-dose acute toxicology study.

Project Terms:
2-Deoxy-2-((methylnitrosoamino)carbonyl)amino-D-glucose; 2-deoxy-2-(3-methyl-3-nitrosoureido)-D-glucopyranose; 2-deoxy-2-[[(methylnitrosamino)-carbonyl]amino]-D-glucopyranose; 21+ years old; ANG-(1-8)Octapeptide; Acute; Adult; Adverse effects; Affect; Age; Albumins; Amidines; AngII; Angiotensin II; Angiotensin-(1-8) Octapeptide; Animal Model; Animal Models and Related Studies; Animals; Attention; Bioavailability; Bioavailable; Biologic Availability; Biological Availability; Blindness; Blood Plasma; Blood Pressure, High; Blood Vessels; Carbamates; Chemicals; Chronic; Clinical; Clinical Trials, Phase II; Common Rat Strains; Complications of Diabetes Mellitus; Data; Development; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Brittle; Diabetes Mellitus, Insulin-Dependent; Diabetes Mellitus, Juvenile-Onset; Diabetes Mellitus, Ketosis-Prone; Diabetes Mellitus, Sudden-Onset; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type I; Diabetes-Related Complications; Diabetic Complications; Diabetic Retinopathy; Dose; Drugs; Esters; Evaluation; Excretory function; Goals; Grant; Human, Adult; Hypertension; IDD; IDDM; In Vitro; Individual; Insulin-Dependent Diabetes Mellitus; Kallikrein I; Lead; Liquid substance; Mammals, Rats; Masks; Medication; Modeling; Oral; Pb element; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Phase 2 Clinical Trials; Phase II Clinical Trials; Physiologic Availability; Plasma; Plasma Kallikrein; Property; Property, LOINC Axis 2; Rat; Rat model of diabetes; Rattus; Reticuloendothelial System, Serum, Plasma; Retinal; Risk; Rodent Model; Route; STZ; Safety; Series; Serine Endopeptidases; Serine Protease; Serine Protein Hydrolases; Serine Proteinases; Serum Kallikrein; Serum, Plasma; Streptozocin; Streptozotocin; System; System, LOINC Axis 4; T1 diabetes; T1D; T1DM; Testing; Therapeutic; Toxicology; Treatment Side Effects; Type 1 diabetes; Uremia; Uremias; Vascular Hypertensive Disease; Vascular Hypertensive Disorder; Vascular Permeabilities; Work; Zanosar; adult human (21+); bioavailability of drug; diabetes; diabetic; diabetic rat; diabetic rat model; drinking water; drug/agent; excretion; fluid; heavy metal Pb; heavy metal lead; hyperpiesia; hyperpiesis; hypertensive disease; improved; in vivo; inhibitor; inhibitor/antagonist; insulin dependent diabetes; juvenile diabetes; juvenile diabetes mellitus; ketosis prone diabetes; kininogenin; lead series; lipophilicity; liquid; macula; macular; macular edema; model organism; novel; phase 2 study; phase 2 trial; phase II trial; pre-clinical; preclinical; protocol, phase II; public health relevance; scaffold; scaffolding; side effect; small molecule; study, phase II; subcutaneous; therapy adverse effect; treatment adverse effect; type I and type II diabetes; type I diabetes; uremia of renal origin; urinary; vascular