Journal of Medicinal Chemistry p. 1346 - 1350 (1986)
Update date:2022-08-05
Topics:
Cho, Moo J.
Sethy, Vimala H.
Haynes, Lynn C.
A 1,4-benzodiazepine analogue alprazolam (1) undergoes ring-opening hydrolysis under acidic conditions to form a triazolobenzophenone (2).At a neutral pH, 2 rapidly and quantitatively cyclizes back to 1.This facile reversible reaction was utilized in developing water-soluble prodrugs of 1 in which the "solubility anchoring" acyl moieties are formyl, acetyl, succinyl, glycyl, leucyl, and γ-aminobutyryl groups.These compounds were prepared directly from 2 and corresponding acids through DCC coupling in a 1:1 mixture of H2O and THF.They should be stable in aqueous media at room temperature.Promoieties used should be nontoxic at an intended dose level.In vitro human serum hydrolysis study showed that only glycyl and leucyl amides were able to regenerate 1 within a reasonable period of time.Ex vivo competitive receptor binding assay in mice with <3H>flunitrazepam indicated that leucyl amide prodrug should be able to produce a rapid onset of the intrinsic central nervous system activity of 1 when parenterally administered.For all compounds studied, the final outcome of the biological response appears to be kinetically controlled, rather than by an unfavorable equilibrium, particularly by the first step in which the amide bond is hydrolyzed in vivo.
View MoreChangsha weichuang chemical co.,ltd
Contact:86-0731-85573222
Address:601,Yongsheng commerce park.No 222.labor East RoadChangSha,HuNan,
Zibo Kunran Enterprises Co. LTD
website:http://www.kunranchem.com
Contact:0086 533 5200669
Address:No. 96 Jinjing Avenue, Zibo, Shandong, China
shanghai longbang industry co.,ltd
Contact:
Address:pudongshanghai
Nanjing Xi Ze Biological Technology Co., Ltd
Contact:86-025-66023220
Address:Address: Nanjin Qixia District Maigaoqiao R & D base in Pioneer Park Chun Yin Road 18-A928
Chemieliva Pharmaceutical Co., Ltd.
website:http://www.chemieliva.com
Contact:+86-23-67770219
Address:99 Longhua Road, Yubei District, 401147, Chongqing, China Email: sales@chemieliva.com Tel:0086-23-67770219 Fax: 0086-23-67770220 Attn: Andy Huang
Doi:10.1021/jo00163a015
(1983)Doi:10.1002/hlca.193702001127
(1937)Doi:10.1021/ja01189a018
(1948)Doi:10.1007/s10870-005-3477-x
(2005)Doi:10.1002/jhet.5570420415
(2005)Doi:10.1016/j.tetasy.2005.04.006
(2005)