246877-30-5Relevant articles and documents
Development of potential preclinical candidates with promising in vitro ADME profile for the inhibition of type 1 and type 2 17β-Hydroxysteroid dehydrogenases: Design, synthesis, and biological evaluation
Abdelsamie, Ahmed S.,Salah, Mohamed,Siebenbürger, Lorenz,Hamed, Mostafa M.,B?rger, Carsten,van Koppen, Chris J.,Frotscher, Martin,Hartmann, Rolf W.
, p. 93 - 107 (2019)
Estrogens are the major female sex steroid hormones, estradiol (E2) being the most potent form in humans. Disturbing the balance between E2 and its weakly active oxidized form estrone (E1) leads to diverse types of estrogen-dependent diseases such as endometriosis or osteoporosis. 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the biosynthesis of E2 by reduction of E1 while the type 2 enzyme catalyzes the reverse reaction. Thus, 17β-HSD1 and 17β-HSD2 are attractive targets for treatment of estrogen-dependent diseases. Recently, we reported the first proof-of-principle study of a 17β-HSD2 inhibitor in a bone fracture mouse model, using subcutaneous administration. In the present study, our aim was to improve the in vitro ADME profile of the most potent 17β-HSD1 and 17β-HSD2 inhibitors described so far. The optimized compounds show strong and selective inhibition of both the human enzymes and their murine orthologs. In addition, they display good metabolic stability in human liver microsomes (S9 fraction), low in vitro cytotoxicity as well as better aqueous solubility and physicochemical properties compared to the lead compounds. These achievements make the compounds eligible for testing in preclinical in vivo animal model studies on the effects of inhibition of 17β-HSD1 and 17β-HSD2.
Structure-activity relationship of HIV-1 protease inhibitors containing α-hydroxy-β-amino acids. Detailed study of P1 site
Takashiro, Eiji,Hayakawa, Ichiro,Nitta, Tamayo,Kasuya, Atsushi,Miyamoto, Shuichi,Ozawa, Yuji,Yagi, Ryuichi,Yamamoto, Ikue,Shibayama, Takahiro,Nakagawa, Akihiko,Yabe, Yuichiro
, p. 2063 - 2072 (2007/10/03)
The structure-activity relationship of HIV-1 protease (HIV-1 PR) inhibitors containing α-hydroxy-β-amino acids is discussed. We demonstrated that substituent groups on the P1 aromatic rings of the inhibitors exert significant influence on their biological activity. Inhibitors bearing an alkyl or a fluorine atom at the meta and para position on their P1 benzene ring were found to be good inhibitors. We also discovered that the substitution positions of the P2 benzamides were crucial for good antiviral potency. In this study, inhibitor 48 was the most potent {IC90 (CEM/HIV-1 IIIB) 27 nM} and showed good pharmacokinetics in rats.
