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

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 r...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2012-04, Vol.22 (7), p.2522-2526
Hauptverfasser:	Kim, Junwon, Ok, Taedong, Park, Changmin, So, Wonyoung, Jo, Mina, Kim, Youngmi, Seo, Minjung, Lee, Doohyun, Jo, Suyeon, Ko, Yoonae, Choi, Inhee, Park, Youngsam, Yoon, Jaewan, Ju, Moon Kyeong, Ahn, JiYe, Kim, Junghwan, Han, Sung-Jun, Kim, Tae-Hee, Cechetto, Jonathan, Nam, Jiyoun, Liuzzi, Michel, Sommer, Peter, No, Zaesung
Format:	Artikel
Sprache:	eng
Schlagworte:	3,4-Dihydropyrimidin-2(1H)-one Animals Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral activity Antiviral agents antiviral properties Biginelli reaction Bioisostere Biological and medical sciences Cell Line, Tumor chemistry Drug Stability Esters HIV HIV Reverse Transcriptase - antagonists & inhibitors HIV-1 - drug effects HIV-1 - physiology Human immunodeficiency virus 1 Humans Inhibitor Life Sciences Medical sciences Microbiology and Parasitology Microsomes, Liver - metabolism Models, Molecular Nevirapine - pharmacology Pharmacology. Drug treatments Pyrimidinones - chemical synthesis Pyrimidinones - pharmacology Rats Replication Reverse Transcriptase Inhibitors - chemical synthesis Reverse Transcriptase Inhibitors - pharmacology scaffolds Structure-Activity Relationship thiazoles Thiazoles - chemistry Virology Virus Replication - drug effects
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Zusammenfassung:	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. 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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.01.133