Asymmetric Synthesis of a Potent HIV-1 Integrase Inhibitor.

The development of a practical asymmetric total synthesis of the potent HIV-1 integrase inhibitor 5 is described. Key transformations include construction of the naphthridine core in a highly efficient manner followed by cyclization of the 8-membered ring. Control of the atropisomers of intermediates and final compound 5 is also described.

Aggregating multiple real-world data sources using a patient-centered health-data-sharing platform.

Real-world data sources, including electronic health records (EHRs) and personal digital device data, are increasingly available, but are often siloed and cannot be easily integrated for clinical, research, or regulatory purposes. We conducted a prospective cohort study of 60 patients undergoing bariatric surgery or catheter-based atrial fibrillation ablation at two U.S. tertiary care hospitals, testing the feasibility of using a patient-centered health-data-sharing platform to obtain and aggregate health data from multiple sources. We successfully obtained EHR data for all patients at both hospitals, as well as from ten additional health systems, which were successfully aggregated with pharmacy data obtained for patients using CVS or Walgreens pharmacies; personal digital device data from activity monitors, digital weight scales, and single-lead ECGs, and patient-reported outcome measure data obtained through surveys to assess post-procedure recovery and disease-specific symptoms. A patient-centered health-data-sharing platform successfully aggregated data from multiple sources.

Overview and experience of the YODA Project with clinical trial data sharing after 5 years.

The Yale University Open Data Access (YODA) Project has facilitated access to clinical trial data since 2013. The purpose of this article is to provide an overview of the Project, describe key decisions that were made when establishing data sharing policies, and suggest how our experience and the experiences of our first two data generator partners, Medtronic, Inc. and Johnson & Johnson, can be used to enhance other ongoing or future initiatives.

Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors.

The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.