title: Synthesis and anti-HIV-1 activity of 4,5,6,7-tetrahydro-5-methylimidazo-[4,5,1-jk][1,4]benzodiazepin- 2(1H)-one (TlBO) derivatives. 4.
abstract: In previous papers, we have described the discovery of a new series of compounds, 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1 H)- ones, TlBO (1 and 1a), with potent anti-HIV-1 activity and the synthesis of analogues to better define the structure-activity relationships (SAR) in terms of changes in substituents at the N-6 position and variations of the five-membered urea ring as well as the seven-membered diazepine ring. This paper describes the synthesis of TlBO analogues with various substitutents on the aromatic ring and their SAR in terms of anti-HIV-1 properties. Substituents on the 8-position furnished the most rewarding results and gave a large improvement in potency versus the parent compound. These included halogen, thiomethyl, and methyl. Analogues like 8-cyano, -methoxy, and -acetylene were equipotent, while 8-amino, -acetylamino, -dimethylamino, and -nitro were inactive (Table 1). Substituents at the 9-position tended to have little effect on activity, and 10-substituents decreased activity. The 8-chloro compound 6a with IC50 = 0.0043 microM is currently under clinical development.
authors.affiliation: Janssen Research Foundation, Spring House, Pennsylvania 19477.
authors.forename: W
authors.initials: W
authors.lastname: Ho
authors.forename: M J
authors.initials: MJ
authors.lastname: Kukla
authors.forename: H J
authors.initials: HJ
authors.lastname: Breslin
authors.forename: D W
authors.initials: DW
authors.lastname: Ludovici
authors.forename: P P
authors.initials: PP
authors.lastname: Grous
authors.forename: C J
authors.initials: CJ
authors.lastname: Diamond
authors.forename: M
authors.initials: M
authors.lastname: Miranda
authors.forename: J D
authors.initials: JD
authors.lastname: Rodgers
authors.forename: C Y
authors.initials: CY
authors.lastname: Ho
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D007093:Imidazoles; D001569:Benzodiazepines