A novel 3,4-dihydropyrimidin-2(1H)-one: HIV-1 replication inhibitors with improved metabolic stability

Junwon Kim; Taedong Ok; Changmin Park; Wonyoung So; Mina Jo; Youngmi Kim; Minjung Seo; Doohyun Lee; Suyeon Jo; Yoonae Ko; Inhee Choi; Youngsam Park; Jaewan Yoon; Moon Kyeong Ju; JiYe Ahn; Junghwan Kim; Sung-Jun Han; Tae-Hee Kim; Jonathan Cechetto; Jiyoun Nam; Michel Liuzzi; Peter Sommer; Zaesung No

doi:10.1016/j.bmcl.2012.01.133

A novel 3,4-dihydropyrimidin-2(1H)-one: HIV-1 replication inhibitors with improved metabolic stability

Bioorg Med Chem Lett. 2012 Apr 1;22(7):2522-6. doi: 10.1016/j.bmcl.2012.01.133. Epub 2012 Feb 8.

Affiliation

¹ Medicinal Chemistry Group, Institut Pasteur Korea, Sampyeong-dong 696, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Republic of Korea.

PMID: 22374216
DOI: 10.1016/j.bmcl.2012.01.133

Abstract

Following the previous SAR of a novel dihydropyrimidinone scaffold as HIV-1 replication inhibitors a detailed study directed towards optimizing the metabolic stability of the ester functional group in the dihydropyrimidinone (DHPM) scaffold is described. Replacement of the ester moiety by thiazole ring significantly improved the metabolic stability while retaining antiviral activity against HIV-1 replication. These novel and potent DHPMs with bioisosteres could serve as advanced leads for further optimization.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Drug Stability
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV-1 / drug effects*
HIV-1 / physiology
Humans
Microsomes, Liver / metabolism
Models, Molecular
Nevirapine / pharmacology
Pyrimidinones / chemical synthesis*
Pyrimidinones / pharmacology
Rats
Reverse Transcriptase Inhibitors / chemical synthesis*
Reverse Transcriptase Inhibitors / pharmacology
Structure-Activity Relationship
Thiazoles / chemistry
Virus Replication / drug effects*

Substances

Pyrimidinones
Reverse Transcriptase Inhibitors
Thiazoles
Nevirapine
HIV Reverse Transcriptase