Discovery of a novel, highly potent and orally bioavailable pyrrolidinone indole series of irreversible Myeloperoxidase (MPO) inhibitors.

Myeloperoxidase (MPO) is a heme-containing peroxidase from phagocytic cells, which plays an important role in the innate immune response. The primary anti-microbial function of MPO is achieved by catalyzing the oxidation of halides by hydrogen peroxide (H2O2). Upon activation of phagocytes, MPO activity is detectable in both phagosomes and extracellularly, where it can remain or transcytose into interstitial compartments. Activated MPO leads to oxidative stress and tissue damage in many inflammatory states, including cardiovascular disease. Starting from a low molecular weight (LMW) high throughput screening (HTS) hit, here we report the discovery of a novel pyrrolidinone indole (IN-4) as a highly potent MPO inhibitor. This compound displays similar in vitro potency across peroxidation, plasma and NETosis assays. In a dilution/dialysis study, <5% of the original MPO activity was detected post-incubation of MPO with IN-4, suggesting irreversible enzyme inhibition. A fast MPO inactivation rate (kinact/Ki) and low partition ratio (k3/k4) make IN-4 kinetic properties attractive for an MPO inhibitor. This compound also displays significant selectivity over the closely related thyroid peroxidase (TPO), and is selective for extracellular MPO over intracellular (neutrophil) MPO. Moreover, IN-4 shows good exposure, low clearance and high oral bioavailability in mice, rats and dogs. The high in vitro MPO activity and high oral exposure observed with IN-4 result in a dose-dependent inhibition of MPO activity in three mouse models of inflammation. In conclusion, IN-4 is a novel, potent, mechanism-based and selective MPO inhibitor, which may be used as superior therapeutic agent to treat multiple inflammatory conditions, including cardiovascular disease.

Successful Strategies for Mitigation of a Preclinical Signal for Phototoxicity in a DGAT1 Inhibitor.

Diacylglycerol O-acyltransferase 1 (DGAT1) inhibitor Pradigastat (1) was shown to be effective at decreasing postprandial triglyceride levels in a patient population with familial chylomicronemia syndrome (FCS). Although pradigastat does not cause photosensitization in humans at the high clinical dose of 40 mg, a positive signal was observed in preclinical models of phototoxicity. Herein, we describe a preclinical phototoxicity mitigation strategy for diarylamine containing molecules utilizing the introduction of an amide or suitable heterocyclic function. This strategy led to the development of two second-generation compounds with low risk of phototoxicity, disparate exposure profiles, and comparable efficacy to 1 in a rodent lipid bolus model for post-prandial plasma triglycerides.

Strategies for pacemaker programming in acute heart failure.

In the past decade, cardiac pacing devices (either permanent pacemakers or Implanted Cardioverter Defibrillators) have become increasingly common in patients with heart failure. The manner in which the device is programmed to pace the heart can have significant implications on cardiac hemodynamics, both positive and negative. As such, in patients hospitalized with acute heart failure who have cardiac pacing devices, the clinician should note whether the programming of the device could be contributing to the patient's symptoms, and whether further programming changes could be made to improve the patient's clinical status. As of this date, there are no consensus guidelines available for the management of pacemaker programming in acute heart failure. This review article will discuss the physiologic implications of several parameters of pacemaker programming on heart failure, including the degree of RV pacing, the programmed atrioventricular (AV) interval, and the programmed interventricular pacing delay in patients with cardiac resynchronization therapy (CRT) devices. Based on the available data on the above parameters, this article will then propose a general algorithmic approach to the evaluation and management of patients with pacing devices who are hospitalized with acute heart failure.

Coronary computed tomography angiography in dialysis patients undergoing pre-renal transplantation cardiac risk stratification.

BACKGROUND: This study addresses the safety, feasibility, and interpretability of coronary computed tomography angiography (CCTA) in excluding significant coronary artery disease in end-stage renal disease patients on dialysis undergoing pre-renal transplant cardiac risk evaluation. METHODS: Twenty nine patients (55.5 +/- 10.2 years) undergoing cardiac risk assessment prior to renal transplantation, underwent research CCTA with calcium scoring and formed the study group. All CCTAs were performed using retrospective acquisition, with beta-blockade provided one hour prior to scanning. RESULTS: No major complications occurred in this group up to 30 days after CCTA. Of the total of 374 segments interpreted by both readers, only 36 (10%) were uninterpretable by both readers. Of these, 31 (86%) were from distal segments or branches. On a segmental level, there was 95% concordance between both readers for < 50% stenosis detection. Only three out of 28 (11%) CCTAs were deemed uninterpretable. Ten patients (36%) had zero calcium score, despite being on dialysis with no evidence of obstructive coronary artery disease by CCTA. CONCLUSIONS: CCTA is feasible and safe in end-stage renal disease dialysis patients with the advent of 64-slice CCTA. Despite significant calcium burden, there was excellent inter-observer agreement at segment level for the left main and all three proximal-mid coronary arteries in excluding obstructive coronary artery disease (> 50% stenosis).