title: Discovery of MK-8970: an acetal carbonate prodrug of raltegravir with enhanced colonic absorption.
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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486 (USA). abbas_walji@merck.com.
authors.forename: Abbas M
authors.initials: AM
authors.lastname: Walji
authors.forename: Rosa I
authors.initials: RI
authors.lastname: Sanchez
authors.forename: Sophie-Dorothee
authors.initials: SD
authors.lastname: Clas
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nofsinger
authors.forename: Manuel
authors.initials: M
authors.lastname: de Lera Ruiz
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Amrithraj
authors.initials: A
authors.lastname: Bennet
authors.forename: Christopher
authors.initials: C
authors.lastname: John
authors.forename: David Jonathan
authors.initials: DJ
authors.lastname: Bennett
authors.forename: John M
authors.initials: JM
authors.lastname: Sanders
authors.forename: Christina N
authors.initials: CN
authors.lastname: Di Marco
authors.forename: Somang Hope
authors.initials: SH
authors.lastname: Kim
authors.forename: Jaume
authors.initials: J
authors.lastname: Balsells
authors.forename: Scott S
authors.initials: SS
authors.lastname: Ceglia
authors.forename: Qun
authors.initials: Q
authors.lastname: Dang
authors.forename: Kimberly
authors.initials: K
authors.lastname: Manser
authors.forename: Becky
authors.initials: B
authors.lastname: Nissley
authors.forename: John S
authors.initials: JS
authors.lastname: Wai
authors.forename: Michael
authors.initials: M
authors.lastname: Hafey
authors.forename: Junying
authors.initials: J
authors.lastname: Wang
authors.forename: Gene
authors.initials: G
authors.lastname: Chessen
authors.forename: Allen
authors.initials: A
authors.lastname: Templeton
authors.forename: John
authors.initials: J
authors.lastname: Higgins
authors.forename: Ronald
authors.initials: R
authors.lastname: Smith
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Wu
authors.forename: Jay
authors.initials: J
authors.lastname: Grobler
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
mesh_terms: D000080:Acetals / Q000737:chemistry; D000818:Animals; D019540:Area Under Curve; D002254:Carbonates / Q000737:chemistry; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D015497:HIV-1 / Q000201:enzymology; D006207:Half-Life; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011760:Pyrrolidinones / Q000737:chemistry*; D012372:ROC Curve; D000068898:Raltegravir Potassium; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D000080:Acetals; D002254:Carbonates; D019428:HIV Integrase Inhibitors; D010069:Oxadiazoles; D011355:Prodrugs; D011744:Pyrimidinones; D011760:Pyrrolidinones; C000601543: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; D000068898:Raltegravir Potassium; D019427:HIV Integrase
keywords: HIV-1; antiviral agents; colonic absorption; controlled-release formulation; once-daily dosing; prodrugs; raltegravir