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Pyrazole NNRTIs 4: selection of UK-453,061 (lersivirine) as a development candidate.

Mowbray, Charles E; Burt, Catherine; Corbau, Romuald; Gayton, Simon; Hawes, Michael; Perros, Manos; Tran, Isabelle; Price, David A; Quinton, Faye J; Selby, Matthew D; Stupple, Paul A; Webster, Rob; Wood, Anthony.

Bioorg Med Chem Lett ; 19(20): 5857-60, 2009 Oct 15.

Article in English | MEDLINE | ID: mdl-19748778

ABSTRACT

We prepared three discreet cohorts of potent non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) based on the recently reported 3-cyanophenoxypyrazole lead 3. Several of these compounds displayed very promising anti-HIV activity in vitro, safety, pharmacokinetic and pharmaceutical profiles. We describe our analysis and conclusions leading to the selection of alcohol 5 (UK-453,061, lersivirine) for clinical development.

Subject(s)

Anti-HIV Agents/chemistry , HIV Reverse Transcriptase/antagonists & inhibitors , Nitriles/chemistry , Pyrazoles/chemistry , Reverse Transcriptase Inhibitors/chemistry , Acquired Immunodeficiency Syndrome/drug therapy , Animals , Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacokinetics , Cell Line , Drug Resistance, Viral , HIV Reverse Transcriptase/metabolism , Humans , Microsomes, Liver/metabolism , Nitriles/chemical synthesis , Nitriles/pharmacokinetics , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Rats , Reverse Transcriptase Inhibitors/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacokinetics

ABSTRACT

Subject(s)

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