- The Chiron Approach to (3 R,3 aS,6 aR)-Hexahydrofuro[2,3- b]furan-3-ol, a Key Subunit of HIV-1 Protease Inhibitor Drug, Darunavir
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We describe an enantioselective synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol which is a key subunit of darunavir, a widely used HIV-1 protease inhibitor drug for the treatment of HIV/AIDS patients. The synthesis was achieved in optically pure form utilizing commercially available sugar derivatives as the starting material. The key steps involve a highly stereoselective substrate-controlled hydrogenation, a Lewis acid catalyzed anomeric reduction of a 1,2-O-isopropylidene-protected glycofuranoside, and a Baeyer-Villiger oxidation of a tetrahydrofuranyl-2-aldehyde derivative. This optically active ligand alcohol was converted to darunavir efficiently.
- Ghosh, Arun K.,Markad, Shivaji B.,Robinson, William L.
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p. 1216 - 1222
(2020/12/22)
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- Design, biologic evaluation, and SAR of novel pseudo-peptide incorporating benzheterocycles as HIV-1 protease inhibitors
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A series of novel HIV-1 protease inhibitors based on the (hydroxyethylamino)-sulfonamide isostere incorporating substituted phenyls and benzheterocycle derivatives bearing rich hydrogen bonding acceptors as P 2 ligands were synthesized. Prolonged chain linking the benzhereocycle to the carbonyl group resulted in partial loss of binding affinities. Introduction of a small alkyl substituent with appropriate size to the -CH2- of P1-P2 linkage as a side chain resulted in improved inhibitory potency, and in this study, isopropyl was the best side chain. Replacement of the isobutyl substituent at P 1′group with phenyl substituent decreased the inhibitory potency. One of the most potent inhibitor, compound 23 showing high affinity to HIV-1 protease with an IC50 value of 5 nm, also exhibited good anti-SIV activity (EC50 = 0.8 μm) with low toxicity (TC 50 > 100 μm). The flexible docking of inhibitor 23 to HIV-1 protease active site rationalized the interactions with protease.
- He, Meizi,Zhang, Hang,Yao, Xiaojian,Eckart, Michael,Zuo, Elizabeth,Yang, Ming
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p. 174 - 180
(2011/03/20)
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- New approaches to the industrial synthesis of HIV protease inhibitors
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Efficient and industrially applicable synthetic processes for precursors of HIV protease inhibitors (Amprenavir, Fosamprenavir) are described. These involve a novel and economical method for the preparation of a key intermediate, (3S)-hydroxytetrahydrofuran, from L-malic acid. Three new approaches to the assembly of Amprenavir are also discussed. Of these, a synthetic route in which an (S)-tetrahydrofuranyloxy carbonyl is attached to L-phenylalanine appears to be the most promising manufacturing process, in that it offers satisfactory stereoselectivity in fewer steps.
- Honda, Yutaka,Katayama, Satoshi,Kojima, Mitsuhiko,Suzuki, Takayuki,Kishibata, Naomi,Izawa, Kunisuke
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p. 2061 - 2070
(2007/10/03)
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- Reduction of peptide character of HIV protease inhibitors that exhibit nanomolar potency against multidrug resistant HIV-1 strains
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Novel HIV protease inhibitors containing a hydroxyethylamine dipeptide isostere as a transition state-mimic king structure were synthesized by combining substructures of known HIV protease inhibitors. Among them, TYA5 and TYB5 were proven to be not only p
- Tamamura, Hirokazu,Koh, Yasuhiro,Ueda, Satoshi,Sasaki, Yoshikazu,Yamasaki, Tomonori,Aoki, Manabu,Maeda, Kenji,Watai, Yoriko,Arikuni, Hisashi,Otaka, Akira,Mitsuya, Hiroaki,Fujii, Nobutaka
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p. 1764 - 1768
(2007/10/03)
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- Bis-amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors
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Selected bis-amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, composition and method for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.
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Page column 51-52
(2008/06/13)
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- Succinoylamino hydroxyethylamino sulfonyl urea derivatives useful as retroviral protease inhibitors
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Succinoylamino hydroxyethylamino sulfonyl urea derivatives of the formula: wherein the substituents are as defined in the specification, are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
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Page column 23
(2010/01/30)
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- A Practical Synthesis of an HIV Protease Inhibitor Intermediate - Diastreoselective Epoxide Formation from Chiral α-Aminoaldehydes
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A practical and efficient synthesis of an HIV protease inhibitor intermediate has been developed based on the diastereoselective epoxide formation from a chiral α-aminoaldehyde and an in situ generated halomethyllithium reagent.
- Ng, John S.,Przybyla, Claire A.,Liu, Chin,Yen, Joe C.,Muellner, Frank W.,Weyker, Cara L.
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p. 6397 - 6410
(2007/10/02)
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