3S85

Discovery of New HIV Protease Inhibitors with Potential for Convenient Dosing and Reduced Side Effects: A-790742 and A-792611.

3S85 の概要

• エントリーDOI: 10.2210/pdb3s85/pdb
• 関連するPDBエントリー: 3gga 3ggv 3ggx
• 関連するBIRD辞書のPRD_ID: PRD_000796
• 分子名称: Protease/reverse transcriptase, methyl N-[(2S)-1-[[(2S,3S,5S)-5-[[(2S)-2-(methoxycarbonylamino)-3,3-dimethyl-butanoyl]amino]-3-oxidanyl-6-phenyl-1-(4-pyridin-3-ylphenyl)hexan-2-yl]amino]-3,3-dimethyl-1-oxidanylidene-butan-2-yl]carbamate (2 entities in total)
• 機能のキーワード: beta barrel, acid protease, aspartic-type endopepidase activity, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Human immunodeficiency virus 1
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 134192.57

構造登録者

DeGoey, D.A.,Flosi, W.J.,Grampovnik, D.J.,Flentge, C.A. (登録日: 2011-05-27, 公開日: 2012-04-11, 最終更新日: 2024-02-28)

主引用文献

Degoey, D.A.,Grampovnik, D.J.,Flentge, C.A.,Flosi, W.J.,Chen, H.J.,Yeung, C.M.,Randolph, J.T.,Klein, L.L.,Dekhtyar, T.,Colletti, L.,Marsh, K.C.,Stoll, V.,Mamo, M.,Morfitt, D.C.,Nguyen, B.,Schmidt, J.M.,Swanson, S.J.,Mo, H.,Kati, W.M.,Molla, A.,Kempf, D.J.
2-Pyridyl P1'-substituted symmetry-based human immunodeficiency virus protease inhibitors (A-792611 and A-790742) with potential for convenient dosing and reduced side effects.
J.Med.Chem., 52:2571-2586, 2009

PubMed Abstract: A series of symmetry-based HIV protease inhibitors was designed and synthesized. Modification of the core regiochemistry and stereochemistry significantly affected the potency, metabolic stability, and oral bioavailability of the inhibitors, as did the variation of a pendent arylmethyl P3 group. Optimization led to the selection of two compounds, 10c (A-790742) and 9d (A-792611), for advancement to preclinical studies. Both compounds displayed low nanomolar potency against wild type HIV in the presence of human serum, low rates of metabolism in human liver microsomes, and high oral bioavailability in animal models. The compounds were examined in a preclinical model for the hyperbilirubinemia observed with some HIV PIs, and both exhibited less bilirubin elevation than comparator compounds. X-ray crystallographic analyses of the new cores were used to examine differences in their binding modes. The antiviral activity of the compounds against protease inhibitor resistant strains of HIV was also determined.

PubMed: 19323562
DOI: 10.1021/jm900044w

実験手法

X-RAY DIFFRACTION (2.8 Å)