Affiliation: | 1. Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486 (USA);2. Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck Research Laboratories, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486 (USA);3. Discovery Pharmaceutical Sciences, Merck Research Laboratories, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486 (USA);4. PharmaSolv Consulting (Montreal, Canada);5. Biopharmaceutics, Pharmaceutical Science, Merck Research Laboratories, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486 (USA);6. Process Chemistry Department, Merck Research Laboratories, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486 (USA);7. Safety Assessment, Merck Research Laboratories, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486 (USA);8. Computational Chemistry, Merck Research Laboratories, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486 (USA);9. Formulation Sciences, Merck Research Laboratories, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486 (USA);10. Department of Virology, Merck Research Laboratories, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486 (USA) |
Abstract: | Developing new antiretroviral therapies for HIV‐1 infection with potential for less frequent dosing represents an important goal within drug discovery. Herein, we present the discovery of ethyl (1‐((4‐((4‐fluorobenzyl)carbamoyl)‐1‐methyl‐2‐(2‐(5‐methyl‐ 1,3,4‐oxadiazole‐2‐carboxamido)propan‐2‐yl)‐6‐oxo‐1,6‐dihydropyrimidin‐5‐yl)oxy)ethyl) carbonate (MK‐8970), a highly optimized prodrug of raltegravir (Isentress). Raltegravir is a small molecule HIV integrase strand‐transfer inhibitor approved for the treatment of HIV infection with twice‐daily administration. Two classes of prodrugs were designed to have enhanced colonic absorption, and derivatives were evaluated in pharmacokinetic studies, both in vitro and in vivo in different species, ultimately leading to the identification of MK‐8970 as a suitable candidate for development as an HIV therapeutic with the potential to require less frequent administration while maintaining the favorable efficacy, tolerability, and minimal drug–drug interaction profile of raltegravir. |