Bristol-Myers Squibb efavirenz

There are a few key enzymes for the proliferation of human immunodeficiency virus (HIV). Reverse transcriptase is one of them since HIV is a member of the DNA viruses. Efavirenz (1) is an orally active non-nucleoside reverse transcriptase inhibitor (NNRTI) and was discovered at Merck Research Laboratories [1] for treatment of HIV infections. Efavirenz was originally licensed to DuPont Merck Pharmaceuticals which was later acquired by Bristol-Myers Squibb.11 The typical adult dose is 600 mg once a day and 1 is one of three key ingredients of the once-a-day oral HIV drug, Atripla (Figure 1.1). 

Currently, Bristol-Myers Squibb is marketing Efavirenz under their brand name of Sustiva and Merck under the brand name of Stocrin . 

USAN Efavirenz (EFV) Trade name Sustiva Bristol-Myers Squibb Launched 1998... 

Sustiva (Efavirenz). Bristol-Myers Squibb Pharmaceuticals Ltd UK Summary of product characteristics, May 2007. 

Hodder SL. Re Important new clinical data. Potential earty virolc c Lhire associated with the combinati on antiretroviral r jmen of tenofovir disopro fumarate, didanosine, and either efavirenz or nevir ine in HTV treatment-naive patients with high baseline viral loads. Bristol-Myers Squibb Company, November 2004. Available at www.fda. v/oashi/aidsdistserv/bnis.pdf (accessed 21/08/07). 

Four compounds DPC-961 (128), DPC-961 (129), DPC-083 (130), and DPC-082 (131) were developed by DuPont Pharmaceuticals as non-nucleoside reverse transcriptase inhibitors. A1 the compounds have reached Phase I clinical trials DPC-083 (130) was further progressed into Phase II trials by Bristol-Myers Squibb after the company had acquired DuPont Pharmaceuticals however, the development was stopped in 2003 due to poor pharmacokinetics [135], The compounds are close analogues of Efavirenz (133) - a non-nucleoside reverse transcriptase inhibitor approved by FDA in 1998 [5], All the compounds 128-131 showed similar to Efavirenz activity towards wild-type virus in vitro however, they were more effective towards singlemutation variants and showed lower plasma serum protein binding [136,137]. 

DPC 961 (134, Scheme 2.21) has shown activity against wild-type HIV-1 and various non-nucleoside reverse transcriptase inhibitor-resistant HIV strains, and with greater potency than the structurally related efavirenz (Sustiva Bristol-Myers Squibb), an approved drug for HIV treat-ment. ° To facilitate the development of DPC 961, researchers at DuPont Pharmaceuticals Company (Wilmington, DE) developed an asymmetric conjugate addition strategy to introduce the trifluoromethyl amine stereocenter. As depicted in Scheme 2.21, treatment of the known aniline 128 ° with two equivalents of (R)-(-l-)-a-methylbenzyl isocyanate 129 afforded the hemiami-nal 130, which was subsequently converted into the 2(3//)-quinazolinone 131 by reaction with thionyl chloride and triethylamine. Reaction of the quinazolinone 131 with excess cyclopropylacetylene magnesium chloride 132 provided the dihydroquinazolinone 133 in 86% yield and 92% diastereomeric excess. Conversion of the dihydroquinazolinone 133 into DPC 961 134 involved treatment with tri-fluoroacetic acid or warm formic acid. Overall, this process provided 16 kg of DPC 961 134 in >55% overall yield from aniline 128. 

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