Synthesis, antiviral activity, and bioavailability studies of γ-lactam derived HIV protease inhibitors

Hungate, Randall W.; Chen, Jenny L.; Starbuck, K.E.; Vacca, Joseph P.; McDaniel, Stacey L.; Levin, Rhonda B.; Dorsey, Bruce D.; Guare, James P.; Holloway, M. Katharine; Whitter, Willie L.; Darke, Paul L.; Zugay, Joan A.; Schleif, William A.; Emini, Emilio A.; Quintero, J. C.; Lin, J H; Chen, I-Wu; Anderson, Paul S.; Huff, Joel R.

doi:10.1016/s0968-0896(00)82037-4

Cited by 17 publications

(4 citation statements)

References 40 publications

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“…This intermediate is the key component in the synthesis of vasicinone, which serves as a remedy for bronchitis and asthma, and its formation here constitutes a formal total synthesis of ( S )-(−)-vasicinone, the most efficient to date 36. γ-Lactams are also known to be potent antibacterial agents,37 HIV protease inhibitors,38 and thrombin inhibitors 39…”

Section: Resultsmentioning

confidence: 99%

A Surprising Mechanistic “Switch” in Lewis Acid Activation: A Bifunctional, Asymmetric Approach to α-Hydroxy Acid Derivatives

et al. 2008

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We report a detailed synthetic and mechanistic study of an unusual bifunctional, sequential heteroDiels-Alder/ring-opening reaction in which chiral, metal complexed ketene enolates react with oquinones to afford highly enantioenriched, α-hydroxylated carbonyl derivatives in excellent yield. A number of Lewis acids were screened in tandem with cinchona alkaloid derivatives; surprisingly, trans-(Ph 3 P) 2 PdCl 2 was found to afford the most dramatic increase in yield and rate of reaction. A series of Lewis acid binding motifs were explored through molecular modeling, as well as IR, UV and NMR spectroscopy. Our observations document a fundamental mechanistic "switch" -namely the formation of a tandem Lewis base/Lewis acid activated metal enolate in preference to a metalcoordinated quinone species (as observed in other reactions of o-quinone derivatives). This new method was applied to the syntheses of several pharmaceutical targets, each of which was obtained in high yield and enantioselectivity.

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Section: Resultsmentioning

confidence: 99%

A Surprising Mechanistic “Switch” in Lewis Acid Activation: A Bifunctional, Asymmetric Approach to α-Hydroxy Acid Derivatives

et al. 2008

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“…Only two compounds ( 118 and 141 ) that were dosed as suspensions in rats gave significant plasma levels. In general, increased aqueous solubility of HIV protease inhibitors has been associated with higher oral bioavailability. ,, However, the superior oral bioavailability of ritonavir suggests that if a solubility threshold that allows formulation as a solution is exceeded, metabolism may play a more important role than aqueous solubility in determining the overall bioavailability and the duration of plasma levels in vivo.…”

Section: Discussionmentioning

confidence: 99%

Discovery of Ritonavir, a Potent Inhibitor of HIV Protease with High Oral Bioavailability and Clinical Efficacy

et al. 1998

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The structure-activity studies leading to the potent and clinically efficacious HIV protease inhibitor ritonavir are described. Beginning with the moderately potent and orally bioavailable inhibitor A-80987, systematic investigation of peripheral (P3 and P2') heterocyclic groups designed to decrease the rate of hepatic metabolism provided analogues with improved pharmacokinetic properties after oral dosing in rats. Replacement of pyridyl groups with thiazoles provided increased chemical stability toward oxidation while maintaining sufficient aqueous solubility for oral absorption. Optimization of hydrophobic interactions with the HIV protease active site produced ritonavir, with excellent in vitro potency (EC50 = 0.02 microM) and high and sustained plasma concentrations after oral administration in four species. Details of the discovery and preclinical development of ritonavir are described.

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“…This intermediate is the key component in the synthesis of ( l )-vasicinone, a drug that serves as a remedy for bronchitis and asthma, and its formation here constitutes a formal total synthesis of ( S )-(−)-vasicinone, the most efficient to date 121. γ-Lactams are also known to be potent antibacterial agents,122 HIV protease inhibitors,123 and thrombin inhibitors 124…”

Section: Asymmetric [4 + 2] Cycloaddition Reactionsmentioning

confidence: 99%

Catalytic, asymmetric reactions of ketenes and ketene enolates

2009

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Synthesis, antiviral activity, and bioavailability studies of γ-lactam derived HIV protease inhibitors

Cited by 17 publications

References 40 publications

A Surprising Mechanistic “Switch” in Lewis Acid Activation: A Bifunctional, Asymmetric Approach to α-Hydroxy Acid Derivatives

A Surprising Mechanistic “Switch” in Lewis Acid Activation: A Bifunctional, Asymmetric Approach to α-Hydroxy Acid Derivatives

Discovery of Ritonavir, a Potent Inhibitor of HIV Protease with High Oral Bioavailability and Clinical Efficacy

Catalytic, asymmetric reactions of ketenes and ketene enolates

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