Altering Metabolic Profiles of Drugs by Precision Deuteration 2: Discovery of a Deuterated Analog of Ivacaftor with Differentiated Pharmacokinetics for Clinical Development.

Ivacaftor is currently used for the treatment of cystic fibrosis as both monotherapy (Kalydeco; Vertex Pharmaceuticals, Boston, MA) and combination therapy with lumacaftor (Orkambi; Vertex Pharmaceuticals). Each therapy targets specific patient populations: Kalydeco treats patients carrying one of nine gating mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, whereas Orkambi treats patients homozygous for the F508del CFTR mutation. In this study, we explored the pharmacological and metabolic effects of precision deuteration chemistry on ivacaftor by synthesizing two novel deuterated ivacaftor analogs, CTP-656 (d9-ivacaftor) and d18-ivacaftor. Ivacaftor is administered twice daily and is extensively converted in humans to major metabolites M1 and M6; therefore, the corresponding deuterated metabolites were also prepared. Both CTP-656 and d18-ivacaftor showed in vitro pharmacologic potency similar to that in ivacaftor, and the deuterated M1 and M6 metabolites showed pharmacology equivalent to that in the corresponding metabolites of ivacaftor, which is consistent with the findings of previous studies of deuterated compounds. However, CTP-656 exhibited markedly enhanced stability when tested in vitro. The deuterium isotope effects for CTP-656 metabolism (DV = 3.8, DV/K = 2.2) were notably large for a cytochrome P450-mediated oxidation. The pharmacokinetic (PK) profile of CTP-656 and d18-ivacaftor were assessed in six healthy volunteers in a single-dose crossover study, which provided the basis for advancing CTP-656 in development. The overall PK profile, including the 15.9-hour half-life for CTP-656, suggests that CTP-656 may be dosed once daily, thereby enhancing patient adherence. Together, these data continue to validate deuterium substitution as a viable approach for creating novel therapeutic agents with properties potentially differentiated from existing drugs.

High-Throughput Screen of Microbial Metabolites Identifies F1FO ATP Synthase Inhibitors as New Leads for Naegleria fowleri Infection.

Primary amebic meningoencephalitis (PAM), a brain infection caused by a free-living ameba Naegleria fowleri, leads to an extensive inflammation of the brain and death within 1-18 (median 5) days after symptoms begin. Although natural products have played a significant role in the development of drugs for over a century, research focusing on identifying new natural product-based anti-N. fowleri agents is limited. We undertook a large-scale ATP bioluminescence-based screen of about 10,000 unique marine microbial metabolite mixtures against the trophozoites of N. fowleri. Our screen identified about 100 test materials with >90% inhibition at 50 µg/mL and a dose-response study found 20 of these active test materials exhibiting an EC50 ranging from 0.2 to 2 µg/mL. Examination of four of these potent metabolite mixtures, derived from our actinomycete strains CNT671, CNT756, and CNH301, resulted in the isolation of a pure metabolite identified as oligomycin D. Oligomycin D exhibited nanomolar potency on multiple genotypes of N. fowleri, and it was five- or 850-times more potent than the recommended drugs amphotericin B or miltefosine. Oligomycin D is fast-acting and reached its EC50 in 10 h, and it was also able to inhibit the invasiveness of N. fowleri significantly when tested on a matrigel invasion assay. Since oligomycin is known to manifest inhibitory activity against F1FO ATP synthase, we tested different F1FO ATP synthase inhibitors and identified a natural peptide leucinostatin as a fast-acting amebicidal compound with nanomolar potency on multiple strains.

A Peculiar Case of Recurrent Coronary Artery Thrombosis.

Coronary artery thrombosis is a phenomenon physicians have studied throughout the years. The different risk factors that play a role in the formation of an atherosclerotic plaque leading to coronary artery blockage are vast and can affect the patient significantly if not examined and diagnosed carefully. The objective of this case report is to highlight this unusual occurrence of repeated coronary artery thrombosis. A 54-year-old Caucasian female presented to the emergency department with a one-day history of sharp chest pain in the substernal area that radiated between her shoulder blades and left arm. Despite being on dual antiplatelet therapy, an electrocardiogram (ECG) showed an inferior ST-elevation myocardial infarction (STEMI). Her medical history was extensive with factor V Leiden deficiency, hyperhomocysteinemia, recurrent deep vein thrombosis (DVT), and a family history of myocardial infarction. The patient was taken to the cardiac catheterization lab based on these characteristics. The patient was diagnosed with a 100% thrombosis in the distal right coronary artery (RCA), which was stented nine months before this current presentation. The patient had been compliant with all her medications from her previous stent placement. A new drug-eluting stent (DES) was inserted, and the patient was placed on prasugrel and apixaban. This was a very interesting topic for a case report due to the time frame of repeat thrombosis in a coronary artery with a DES and the patient's underlying hypercoagulable state. There are few cases of same vessel restenosis post-DES placement. Our case highlights the need for further research into the prevalence of genetic risk factors in coronary artery thrombosis and the need to investigate the efficacy of different anticoagulation therapies in patients with factor V Leiden thrombophilia.