Novel non-nucleoside inhibitors of HIV-1 reverse transcriptase. 2. Tricyclic pyridobenzoxazepinones and dibenzoxazepinones

• Published in: Journal of medicinal chemistry 1992-05, Vol.35 (10), p.1887-1897
• Main Authors: Klunder, Janice M, Hargrave, Karl D, West, MaryAnn, Cullen, Ernest, Pal, Kollol, Behnke, Mark L, Kapadia, Suresh R, McNeil, Daniel W, Wu, Joe C, Chow, Grace C, Adams, Julian
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Dibenzoxazepines - chemistry; Dibenzoxazepines - pharmacology; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; HIV-1 - enzymology; human immunodeficiency virus 1; Recombinant Proteins - antagonists & inhibitors; Reverse Transcriptase Inhibitors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00088a027

Dibenz[b,f][1,4]oxazepin-11(10H)-ones (III), pyrido[2,3-b][1,4]benzoxazepin-6(5H)-ones (IV), and pyrido[2,3-b]- [1,5]benzoxazepin-5(6H)-ones (V) were found to inhibit human immunodeficiency virus type 1 reverse transcriptase with IC50 values as low as 19 nM. A-ring substitution has a profound effect on activity, with appropriate substituents at the positions ortho and para to the lactam nitrogen providing dramatically enhanced potency. Substitution in the C-ring is generally neutral or detrimental to activity. Although a C-ring amino substituent at the position meta to the lactam carbonyl is generally beneficial to activity, it has essentially no effect when the A-ring is optimally substituted. Like the dipyridodiazepinone nevirapine, compounds III-V are specific for HIV-1 RT, exhibiting no inhibitory activity against HIV-2 RT or other virial reverse transcriptase enzymes.