Identification of substituted benzothiazole sulfones as potent and selective inhibitors of endothelial lipase.

A low level of high density lipoprotein (HDL) is an independent risk factor for cardiovascular disease. HDL reduces inflammation and plays a central role in reverse cholesterol transport, where cholesterol is removed from peripheral tissues and atherosclerotic plaque. One approach to increase plasma HDL is through inhibition of endothelial lipase (EL). EL hydrolyzes phospholipids in HDL resulting in reduction of plasma HDL. A series of benzothiazole sulfone amides was optimized for EL inhibition potency, lipase selectivity and improved pharmacokinetic profile leading to the identification of Compound 32. Compound 32 was evaluated in a mouse pharmacodynamic model and found to show no effect on HDL cholesterol level despite achieving targeted plasma exposure (Ctrough > 15 fold over mouse plasma EL IC50 over 4 days).

Comparison of Prescribing Practices with Direct Acting Oral Anticoagulant Protocols.

BACKGROUND: The goal of anticoagulation management programs is to prevent thrombosis while minimizing the risks of hemorrhage. Direct acting oral anticoagulants (DOACs) selectively inhibit coagulation proteins to inhibit thrombosis. Previous studies suggest patient monitoring and education provided through anticoagulation services enhance adherence and decrease adverse outcomes in patients receiving DOAC therapy. OBJECTIVE: The objectives of this study were to describe DOAC prescribing adherence to anticoagulation service protocols and to observe whether enrollment in an anticoagulation service resulted in greater prescribing adherence to DOAC protocols. METHODS: A retrospective cohort study evaluated all initial prescriptions of apixaban, dabigatran, and rivaroxaban at Marshfield Clinic from 19 October 2010 to 21 August 2014. Three algorithms analyzed patient and prescription data extracted from the organization's electronic health record and classified prescriptions as per protocol or not per protocol. The algorithms classified not per protocol prescriptions as off-label indication, renal impairment [estimated glomerular filtration rate (eGFR) <30 ml/min], hepatic impairment (rivaroxaban and apixaban), advanced age >74 years (dabigatran), dose too low, or dose too high. The analysis assessed whether enrollment in the Marshfield Clinic Anticoagulation Service DOAC monitoring process was associated with increased adherence to protocols. RESULTS: In aggregate, 72% of apixaban prescriptions, 52% of dabigatran prescriptions, and 70% of rivaroxaban prescriptions were per protocol. Off-label indications and dosage too low were the most common not per protocol reasons for apixaban and rivaroxaban prescriptions. Age ≥75 years and off-label indication were the most common not per protocol reasons for dabigatran prescriptions. Enrollment in the anticoagulation service process was not associated with increased adherence to protocols. CONCLUSION: A significant proportion of DOAC prescriptions did not adhere to protocol expectations. While enrollment in DOAC management through the Marshfield Clinic Anticoagulation Service was not associated with increased adherence to protocols, opportunities exist to optimize DOAC prescribing. Defining ideal DOAC management requires additional research.

Neutral macrocyclic factor VIIa inhibitors.

Factor VIIa (FVIIa) inhibitors have shown strong antithrombotic efficacy in preclinical thrombosis models with limited bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful due to the requirement of a basic P1 group to interact with Asp189 in the S1 binding pocket, limiting their membrane permeability. We have combined recently reported neutral P1 binding substituents with a highly optimized macrocyclic chemotype to produce FVIIa inhibitors with low nanomolar potency and enhanced permeability.

Discovery of Phenylglycine Lactams as Potent Neutral Factor VIIa Inhibitors.

Inhibitors of Factor VIIa (FVIIa), a serine protease in the clotting cascade, have shown strong antithrombotic efficacy in preclinical thrombosis models with minimal bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful because known chemotypes have required a highly basic group in the S1 binding pocket for high affinity. A recently reported fragment screening effort resulted in the discovery of a neutral heterocycle, 7-chloro-3,4-dihydroisoquinolin-1(2H)-one, that binds in the S1 pocket of FVIIa and can be incorporated into a phenylglycine FVIIa inhibitor. Optimization of this P1 binding group led to the first series of neutral, permeable FVIIa inhibitors with low nanomolar potency.

Discovery of a Highly Potent, Selective, and Orally Bioavailable Macrocyclic Inhibitor of Blood Coagulation Factor VIIa-Tissue Factor Complex.

Inhibitors of the tissue factor (TF)/factor VIIa complex (TF-FVIIa) are promising novel anticoagulants which show excellent efficacy and minimal bleeding in preclinical models. Starting with an aminoisoquinoline P1-based macrocyclic inhibitor, optimization of the P' groups led to a series of highly potent and selective TF-FVIIa inhibitors which displayed poor permeability. Fluorination of the aminoisoquinoline reduced the basicity of the P1 group and significantly improved permeability. The resulting lead compound was highly potent, selective, and achieved good pharmacokinetics in dogs with oral dosing. Moreover, it demonstrated robust antithrombotic activity in a rabbit model of arterial thrombosis.