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How was synthetiside drug crixivan?

Asymmetric hydrogenation

Fries rearrangement

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The synthesis of the antiretroviral drug Crixivan involved a multi-step process. Initially, a chiral hydrogenation step was utilized to establish the absolute stereochemistry of a tetrahydropyrazine intermediate . Subsequently, a series of analogs containing various aromatic ligands were prepared and evaluated for their inhibitory activity against the HIV-1 protease enzyme, with these compounds showing effectiveness at nanomolar concentrations in both in vitro and whole cell assays . The development of Crixivan was driven by the need to improve the oral bioavailability of early HIV-1 protease inhibitors. By incorporating increased polarity into the inhibitor backbone, a series of potent inhibitors with enhanced aqueous solubility and improved bioavailability were achieved, ultimately leading to the discovery of Crixivan as a widely used treatment for AIDS .

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Open access•Dissertation Synthetic Studies Towards the Crisamicins Michelle Yu Huay Lai 01 Jan 2002 2 Citations	Not addressed in the paper.
Journal Article•DOI Aromatic P1 Replacements for the Highly Potent HIV-1 Protease Inhibitor Crixivan. Craig A. Coburn, Mary Beth Young, Hungate Randall W, Richard C.A. Isaacs, Joseph P. Vacca, Joel R. Huff - Show less +5 more 04 Aug 2010-ChemInform	The synthesis of CRIXIVAN involved preparing analogs with aromatic P1 ligands, resulting in potent HIV-1 protease inhibition at nanomolar concentrations in both enzyme and whole cell assays.
Book Chapter•DOI The integration of medicinal chemistry, drug metabolism, and pharmaceutical research and development in drug discovery and development. The story of Crixivan, an HIV protease inhibitor. Jiunn H. Lin, Drazen Ostovic, Joseph P. Vacca - Show less +2 more 01 Jan 2002-Pharmaceutical biotechnology 22 Citations	Crixivan was synthesized by incorporating increased polarity into the inhibitor backbone, enhancing aqueous solubility without compromising potency, leading to improved bioavailability and successful treatment of AIDS.
Journal Article•DOI An Efficient Asymmetric Hydrogenation Approach to the Synthesis of the Crixivan® Piperazine Intermediate. Kai Rossen, P. J. Pye, Lisa DiMichele, Ralph P. Volante, Paul J. Reider - Show less +4 more 08 Dec 1998-ChemInform 5 Citations	The Crixivan® piperazine intermediate was synthesized efficiently through a four-step sequence, including a chiral hydrogenation of tetrahydropyrazine to establish absolute stereochemistry.
Journal Article•DOI "Multi-component reactions : emerging chemistry in drug discovery" 'from xylocain to crixivan'. Christopher Hulme, Vijay Keshav Gore - Show less +1 more 01 Jan 2003-Current Medicinal Chemistry 927 Citations	Crixivan, a synthetiside drug, was synthesized using multi-component reactions (MCR), specifically isocyanide based MCR (IMCR) reactions, showcasing efficient and cost-effective drug discovery methodologies.

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