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Discovery of MK‐8970: An Acetal Carbonate Prodrug of Raltegravir with Enhanced Colonic Absorption
Author(s) -
Walji Abbas M.,
Sanchez Rosa I.,
Clas SophieDorothee,
Nofsinger Rebecca,
de Lera Ruiz Manuel,
Li Jing,
Bennet Amrithraj,
John Christopher,
Bennett David Jonathan,
Sanders John M.,
Di Marco Christi.,
Kim Somang Hope,
Balsells Jaume,
Ceglia Scott S.,
Dang Qun,
Manser Kimberly,
Nissley Becky,
Wai John S.,
Hafey Michael,
Wang Junying,
Chessen Gene,
Templeton Allen,
Higgins John,
Smith Ronald,
Wu Yunhui,
Grobler Jay,
Coleman Paul J.
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402393
Subject(s) - raltegravir , prodrug , pharmacology , pharmacokinetics , drug , chemistry , in vivo , tolerability , drug discovery , human immunodeficiency virus (hiv) , medicine , adverse effect , antiretroviral therapy , biochemistry , virology , biology , viral load , microbiology and biotechnology
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.