162537-11-3Relevant articles and documents
Coupling of an Acyl Migration Prodrug Strategy with Bio-activation to Improve Oral Delivery of the HIV-1 Protease Inhibitor Atazanavir
Subbaiah, Murugaiah A. M.,Meanwell, Nicholas A.,Kadow, John F.,Subramani, Lakshumanan,Annadurai, Mathiazhagan,Ramar, Thangeswaran,Desai, Salil D.,Sinha, Sarmistha,Subramanian, Murali,Mandlekar, Sandhya,Sridhar, Srikanth,Padmanabhan, Shweta,Bhutani, Priyadeep,Arla, Rambabu,Jenkins, Susan M.,Krystal, Mark R.,Wang, Chunfu,Sarabu, Ramakanth
, p. 4176 - 4188 (2018)
HIV-1 protease inhibitors (PIs), which include atazanavir (ATV, 1), remain important medicines to treat HIV-1 infection. However, they are characterized by poor oral bioavailability and a need for boosting with a pharmacokinetic enhancer, which results in additional drug-drug interactions that are sometimes difficult to manage. We investigated a chemo-activated, acyl migration-based prodrug design approach to improve the pharmacokinetic profile of 1 but failed to obtain improved oral bioavailability over dosing the parent drug in rats. This strategy was refined by conjugating the amine with a promoiety designed to undergo bio-activation, as a means of modulating the subsequent chemo-activation. This culminated in a lead prodrug that (1) yielded substantially better oral drug delivery of 1 when compared to the parent itself, the simple acyl migration-based prodrug, and the corresponding simple l-Val prodrug, (2) acted as a depot which resulted in a sustained release of the parent drug in vivo, and (3) offered the benefit of mitigating the pH-dependent absorption associated with 1, thereby potentially reducing the risk of decreased bioavailability with concurrent use of stomach-acid-reducing drugs.
PROTEASE INHIBITORS HAVING ENHANCED FEATURES
-
Paragraph 0136, (2017/02/28)
Provided herein (among other things) are protease inhibitor compounds having enhanced features, along with methods for administering such compounds. For example, the subject compounds can be administered without concomitant administration of a CYP3A4 inhibitor, have increased therapeutic index and/or increased potency, and are low-resistance inducing in nature.
9,9,10,10-TETRAFLUORO-9,10-DIHYDROPHENANTHRENE HEPATITIS C VIRUS INHIBITOR AND APPLICATION THEREOF
-
Paragraph 0154-0156, (2016/10/31)
The present invention belongs to the field of chemical pharmaceuticals, and specifically relates to compounds represented by formula I having a 9,9,10,10-tetrafluoro-9,10-dihydrophenanthrene structure and being able to inhibit hepatitis C virus activity, or a pharmaceutically acceptable salt, isomer, solvate, crystal or prodrug of said compounds, a pharmaceutical composition containing said compounds, and an application of said compounds or composition in the preparation of a drug. The compounds of the present invention have a good HCV inhibitory effect.
