Discovery of Novel Reductive Elimination Pathway for 10-Hydroxywarfarin

Coumadin (R/S-warfarin) anticoagulant therapy is highly efficacious in preventing the formation of blood clots; however, significant inter-individual variations in response risks over or under dosing resulting in adverse bleeding events or ineffective therapy, respectively. Levels of pharmacologically active forms of the drug and metabolites depend on a diversity of metabolic pathways. Cytochromes P450 play a major role in oxidizing R- and S-warfarin to 6-, 7-, 8-, 10-, and 4′-hydroxywarfarin, and warfarin alcohols form through a minor metabolic pathway involving reduction at the C11 position. We hypothesized that due to structural similarities with warfarin, hydroxywarfarins undergo reduction, possibly impacting their pharmacological activity and elimination. We modeled reduction reactions and carried out experimental steady-state reactions with human liver cytosol for conversion of rac-6-, 7-, 8-, 4′-hydroxywarfarin and 10-hydroxywarfarin isomers to the corresponding alcohols. The modeling correctly predicted the more efficient reduction of 10-hydroxywarfarin over warfarin but not the order of the remaining hydroxywarfarins. Experimental studies did not indicate any clear trends in the reduction for rac-hydroxywarfarins or 10-hydroxywarfarin into alcohol 1 and 2. The collective findings indicated the location of the hydroxyl group significantly impacted reduction selectivity among the hydroxywarfarins, as well as the specificity for the resulting metabolites. Based on studies with R- and S-7-hydroxywarfarin, we predicted that all hydroxywarfarin reductions are enantioselective toward R substrates and enantiospecific for S alcohol metabolites. CBR1 and to a lesser extent AKR1C3 reductases are responsible for those reactions. Due to the inefficiency of reactions, only reduction of 10-hydroxywarfarin is likely to be important in clearance of the metabolite. This pathway for 10-hydroxywarfarin may have clinical relevance as well given its anticoagulant activity and capacity to inhibit S-warfarin metabolism.

First-in-Human Evaluation of the Safety, Tolerability, and Pharmacokinetics of SPR720, a Novel Oral Bacterial DNA Gyrase (GyrB) Inhibitor for Mycobacterial Infections

SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial pulmonary disease (NTM-PD) and pulmonary tuberculosis. SPR719 has demonstrated activity against clinically relevant mycobacteria in vitro and in murine and hollow fiber infection models. This Phase 1 randomized, double-blind, placebo-controlled, single ascending dose (SAD)/multiple ascending dose (MAD) trial evaluated the safety, tolerability, and pharmacokinetics of SPR720/SPR719. A total of 96 healthy volunteers (n=8/cohort, 3:1 randomization) received SPR720 (or placebo) as single oral doses ranging from 100 mg to 2000 mg, or repeat total daily doses ranging from 500 mg to 1500 mg for 7 or 14 days. SPR720 was well-tolerated at daily doses up to 1000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events (AEs) were gastrointestinal (nausea, vomiting and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious adverse events were reported. The median SPR719 T max ranged from 2.8 to 8.0 hours across cohorts, and the t 1/2 ranged from 2.9 to 4.5 hours and was shown to be dose-independent. Dosing with food decreased SPR719 plasma exposure by approximately 20%. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between Days 1 and 7, suggesting induction of an elimination pathway. However, plasma AUC 0-24 was comparable between Days 7 and 14. Results of this first-in-human study suggest that predicted therapeutic exposures of SPR719 can be attained with a once-daily oral administration of SPR720.

Comparing Potential Drug–Drug Interactions in Companion Animal Medications Using Two Electronic Databases

Multiple-drug prescriptions can cause drug–drug interactions (DDIs), which increase risks associated with healthcare in veterinary medicine. Moreover, many human medicines are used in canine patients under the responsibility of veterinarians and may cause severe problems due to off-label use. Currently, many electronic databases are being used as tools for potential DDI prediction, for example, Micromedex and Drugs.com, which may benefit the prediction of potential DDIs for drugs used in canine. The purpose of this study was to examine different abilities for the identification of potential DDIs in companion animal medicine, especially in canine patients, by Micromedex and Drugs.com. Micromedex showed 429 pairs of potential DDIs, while Drugs.com showed 842 pairs of potential DDIs. The analysis comparing results between the two databases showed 139 pairs (12.28%) with the same severity and 993 pairs (87.72%) with different severities. The major mechanisms of contraindicated and major potential DDIs were cytochrome P450 induction–inhibition and QT interval prolongation. Veterinarians should interpret potential DDIs from several databases with caution and keep in mind that the results might not be reliable due to differences in sensitivity to drugs, drug-metabolizing enzymes, and elimination pathway between animals and humans.

Nickel-Copper Co-Catalyzed Sustainable Synthesis of Diaryl- Chalcogenides

Abstract:: In recent times, Nickel has become a powerful alternative transition metal catalyst for performing cross-coupling reactions due to its low cost and better sustainability. Thus a sustainable Ni-catalyzed C-Se cross coupling has been developed in presence of catalytic amount of copper iodide as co-catalyst. A wide range of substituted diaryl selenides have been synthesized by this Ni-Cu dual catalyzed C-Se cross coupling. The reaction is following an oxidative addition and reductive elimination pathway where Cu is playing an important role in transmetalation. The mechanism of the reaction was established by several experimental techniques.

New Strategies in the Design of Paramagnetic CAs

Nowadays, magnetic resonance imaging (MRI) is the first diagnostic imaging modality for numerous indications able to provide anatomical information with high spatial resolution through the use of magnetic fields and gradients. Indeed, thanks to the characteristic relaxation time of each tissue, it is possible to distinguish between healthy and pathological ones. However, the need to have brighter images to increase differences and catch important diagnostic details has led to the use of contrast agents (CAs). Among them, Gadolinium-based CAs (Gd-CAs) are routinely used in clinical MRI practice. During these last years, FDA highlighted many risks related to the use of Gd-CAs such as nephrotoxicity, heavy allergic effects, and, recently, about the deposition within the brain. These alerts opened a debate about the opportunity to formulate Gd-CAs in a different way but also to the use of alternative and safer compounds to be administered, such as manganese- (Mn-) based agents. In this review, the physical principle behind the role of relaxivity and the T1 boosting will be described in terms of characteristic correlation times and inner and outer spheres. Then, the recent advances in the entrapment of Gd-CAs within nanostructures will be analyzed in terms of relaxivity boosting obtained without the chemical modification of CAs as approved in the chemical practice. Finally, a critical evaluation of the use of manganese-based CAs will be illustrated as an alternative ion to Gd due to its excellent properties and endogenous elimination pathway.

A Computational Study of the Hofmann Elimination Pathway for the MoritaBaylis-Hillman Reaction Under DABCO Catalysis. Participation of a Bridge-Head Ylide

In comparison to the popular pathway involving proton-transfer via a four-centred cyclic transition state structure, the recently proposed overall lower energy pathway involving proton-transfer via a seven-centred cyclic transition state structure followed by Hofmann elimination for the Me₃N-catalyzed Morita-Baylis-Hillman reaction is applicable to the DABCO-catalyzed reaction equally well. This finding clearly establishes that the zwitterion at the bridge-head in DABCO is well tolerated. Also, the activation free energy of the rate-limiting aldol reaction under DABCO-catalysis is lower than that under Me₃N-catalysis, suggesting that DABCO is likely a better catalyst to achieve faster conversion.

A Computational Study of the Hofmann Elimination Pathway for the MoritaBaylis-Hillman Reaction Under DABCO Catalysis. Participation of a Bridge-Head Ylide

In comparison to the popular pathway involving proton-transfer via a four-centred cyclic transition state structure, the recently proposed overall lower energy pathway involving proton-transfer via a seven-centred cyclic transition state structure followed by Hofmann elimination for the Me₃N-catalyzed Morita-Baylis-Hillman reaction is applicable to the DABCO-catalyzed reaction equally well. This finding clearly establishes that the zwitterion at the bridge-head in DABCO is well tolerated. Also, the activation free energy of the rate-limiting aldol reaction under DABCO-catalysis is lower than that under Me₃N-catalysis, suggesting that DABCO is likely a better catalyst to achieve faster conversion.