329944-30-1Relevant academic research and scientific papers
Structure-activity relationship studies of novel benzophenones leading to the discovery of a potent, next generation HIV nonnucleoside reverse transcriptase inhibitor
Romines, Karen R.,Freeman, George A.,Schaller, Lee T.,Cowan, Jill R.,Gonzales, Steve S.,Tidwell, Jeffrey H.,Andrews III, Clarence W.,Stammers, David K.,Hazen, Richard J.,Ferris, Robert G.,Short, Steven A.,Chan, Joseph H.,Boone, Lawrence R.
, p. 727 - 739 (2007/10/03)
Despite the progress of the past two decades, there is still considerable need for safe, efficacious drugs that target human immunodeficiency virus (HIV). This is particularly true for the growing number of patients infected with virus resistant to currently approved HIV drugs. Our high throughput screening effort identified a benzophenone template as a potential nonnucleoside reverse transcriptase inhibitor (NNRTI). This manuscript describes our extensive exploration of the benzophenone structure-activity relationships, which culminated in the identification of several compounds with very potent inhibition of both wild type and clinically relevant NNRTI-resistant mutant strains of HIV. These potent inhibitors include 70h (GW678248), which has in vitro antiviral assay IC50 values of 0.5 nM against wild-type HIV, 1 nM against the K103N mutant associated with clinical resistance to efavirenz, and 0.7 nM against the Y181C mutant associated with clinical resistance to nevirapine. Compound 70h has also demonstrated relatively low clearance in intravenous pharmacokinetic studies in three species, and it is the active component of a drug candidate which has progressed to phase 2 clinical studies.
Novel Benzophenones as Non-nucleoside Reverse Transcriptase Inhibitors of HIV-1
Chan, Joseph H.,Freeman, George A.,Tidwell, Jeffrey H.,Romines, Karen R.,Schaller, Lee T.,Cowan, Jill R.,Gonzales, Steve S.,Lowell, Gina S.,Andrews III,Reynolds, David J.,St. Clair, Marty,Hazen, Richard J.,Ferris, Rob G.,Creech, Katrina L.,Roberts, Grace B.,Short, Steven A.,Weaver, Kurt,Koszalka, George W.,Boone, Lawrence R.
, p. 1175 - 1182 (2007/10/03)
GW4511, GW4751, and GW3011 showed IC50 values ≤2 nM against wild type HIV-1 and 10 nM against 16 mutants. They were particularly potent against NNRTI-resistant viruses containing Y181C-, K103N-, and K103N-based double mutations, which account for a significant proportion of the clinical failure of the three currently marketed NNRTIs. The antiviral data together with the favorable pharmacokinetic data of GW4511 suggested that these benzophenones possess attributes of a new NNRTI drug candidate.
