Design and Synthesis of Potent<i>C</i><sub>2</sub>-Symmetric Diol-Based HIV-1 Protease Inhibitors:  Effects of Fluoro Substitution

Pyring, David; Lindberg, Jimmy; Rosenquist, Åsa; Zuccarello, Guido; Kvarnström, Ingemar; Zhang, Hong; Vrang, Lotta; Unge, Torsten; Classon, Björn; Hallberg, A.; Samuelsson, Bertil

doi:10.1021/jm001134q

Cited by 29 publications

(27 citation statements)

References 44 publications

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“…The linear C2‐symmetric inhibitors in this study encompass a six‐carbon chiral center derived from l ‐mannaric acid. The five P1/P1′ fluoro‐substituted C2‐symmetric inhibitors 2–6 were synthesized based on the nonsubstituted analog; 1 with benzyloxy side groups in P1/P1′ and indanolamine side groups in P2/P2′[33]. All inhibitors have K i values within the nanomolar to picomolar range, and antiviral activity expressed as ED 50 values varying from 100 to 20 n m (Table 3).…”

Section: Inhibitor Propertiesmentioning

confidence: 99%

Symmetric fluoro‐substituted diol‐based HIV protease inhibitors

Lindberg

Pyring

Löwgren

et al. 2004

European Journal of Biochemistry

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HIV-1 protease is a pivotal enzyme in the later stages of the viral life cycle which is responsible for the processing and maturation of the virus particle into an infectious virion. As such, HIV-1 protease has become an important target for the treatment of AIDS, and efficient drugs have been developed. However, negative side effects and fast emerging resistance to the current drugs have necessitated the development of novel chemical entities in order to exploit different pharmacokinetic properties as well as new interaction patterns. We have used X-ray crystallography to decipher the structure-activity relationship of fluoro-substitution as a strategy to improve the antiviral activity and the protease inhibition of C2-symmetric diol-based inhibitors. In total we present six protease-inhibitor complexes at 1.8-2.3 Å resolution, which have been structurally characterized with respect to their antiviral and inhibitory activities, in order to evaluate the effects of different fluoro-substitutions. These C2-symmetric inhibitors comprise mono-and difluoro-substituted benzyloxy side groups in P1/P1¢ and indanoleamine side groups in P2/P2¢. The ortho-and meta-fluorinated P1/P1¢-benzyloxy side groups proved to have the most cytopathogenic effects compared with the nonsubstituted analog and related C2-symmetric diol-based inhibitors. The different fluorosubstitutions are well accommodated in the protease S1/S1¢ subsites, as observed by an increase in favorable Van der Waals contacts and surface area buried by the inhibitors. These data will be used in the development of potent inhibitors with different pharmacokinetic profiles towards resistant protease mutants.

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Section: Inhibitor Propertiesmentioning

confidence: 99%

Symmetric fluoro‐substituted diol‐based HIV protease inhibitors

Lindberg

Pyring

Löwgren

et al. 2004

European Journal of Biochemistry

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“…5 Though inhibition of HIV-protease is generally paralleled by a reduced rate of HIV replication in cell culture, the correlation between inhibition constants (K i ) and ED 50 values is in fact rather poor. For example, data for C 2 -symmetric compounds 5,6 reveal not only a poor correlation but also differences between structural classes of inhibitors ( Figure 1). An analysis with a larger set of compounds of even greater diversity also showed a poor correlation between cell culture and inhibition data, 7 indicating that this is a general problem not limited to the C 2 -symmetric compounds.…”

Section: Introductionmentioning

confidence: 99%

“…11 To our knowledge, there are no studies that (9) and B369 analogues (9), 6 P1/P1′ analogues of B268 ([), 5 and references (saquinavir, ritonavir, and nelfinavir) (2). 6 address the weak correlation between inhibition of wildtype enzyme and viral replication.…”

Section: Introductionmentioning

confidence: 99%

Improved Structure−Activity Relationship Analysis of HIV-1 Protease Inhibitors Using Interaction Kinetic Data

2004

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Despite the availability of large amounts of data for HIV-protease inhibitors and their effectiveness with wild type and resistant enzyme, there is limited knowledge about how this and other information can be systematically applied to the development of new antiviral compounds. To identify in vitro parameters that correlate with the efficacy of HIV inhibitors in cell culture, the relationships between inhibition, interaction kinetic, and cell culture parameters for HIV-1 protease inhibitors were analyzed. Correlation, cluster, and principal component analysis of data for 37 cyclic and linear compounds revealed that the affinities (K(D)) determined from SPR-biosensor binding studies correlated better to cell culture efficacy (ED(50)) than that of the inhibition constants (K(i)), indicating that the conventional use of K(i) values for structure-activity relationship analysis of HIV-1 inhibitors should be seriously reconsidered. The association and dissociation kinetic rate constants (k(on) and k(off)) alone showed weak correlations with ED(50) values. However, ED(50) values were most related to the free enzyme concentration in the viral particle ([E]), calculated from the rate constants and the total enzyme concentration in a viral particle. A structure-activity relationship analysis of the current data set was found to be valid for all classes of compounds analyzed. In summary, use of affinity, based on interaction kinetic rate constants, rather than inhibition constants, and theoretical consideration of the physiological conditions in the virus particle provide improved structure-activity relationship analysis of HIV-1 protease inhibitors.

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“…Additional optimization at P 1 identified the 3, 5-difluorobenzyl substituent as a preferred group. Enhanced cell penetration has been noted for fluorinated benzyl groups within the context of HIV-protease inhibitors [31]. The combination of these fragments produced compound 5 (Fig.…”

Section: Transition-state Analog Inhibitors Statinesmentioning

confidence: 92%

“…Fig. (16) within the context of HIV-protease inhibitors [31]. Compound 32 is the direct analog of the hydroxyethylene isostere, with the same stereochemistry at P 1 and the C 2 hydroxyl (anti), an ethyl group in P 1 ' and a carboxylatecontaining prime side binding element similar to the Elan cyclohexyl carboxylate fragment.…”

Section: Hydroxyethylamine Isosteresmentioning

confidence: 99%

Progress in the Discovery of BACE Inhibitors

Thompson¹,

Bronson²,

Zusi³

2005

CPD

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Dementia caused by Alzheimer's disease is a large medical burden on society in the developed world. Current treatments are largely symptomatic, and there is an urgent need for therapies which can interrupt or reverse the progression of disease. A number of strategies for intervention are being actively pursued; among the most promising is the inhibition of beta-secretase, or BACE. BACE is the enzyme responsible for N-terminal cleavage of the Alzheimer's precursor protein leading to the production of the beta-amyloid peptide. This cascade ultimately leads to the formation of amyloid plaques, one of the hallmark lesions of the disease. It is expected that inhibitors of BACE may therefore serve as an effective disease-modifing therapy for the treatment of AD. This concept has received significant attention by both academics and the pharmaceutical industry. This review focuses on a discussion of the reported structure-activity relationships for inhibitors of this important therapeutic target.

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Design and Synthesis of PotentC₂-Symmetric Diol-Based HIV-1 Protease Inhibitors: Effects of Fluoro Substitution

Cited by 29 publications

References 44 publications

Symmetric fluoro‐substituted diol‐based HIV protease inhibitors

Symmetric fluoro‐substituted diol‐based HIV protease inhibitors

Improved Structure−Activity Relationship Analysis of HIV-1 Protease Inhibitors Using Interaction Kinetic Data

Progress in the Discovery of BACE Inhibitors

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Design and Synthesis of PotentC2-Symmetric Diol-Based HIV-1 Protease Inhibitors: Effects of Fluoro Substitution

Cited by 29 publications

References 44 publications

Symmetric fluoro‐substituted diol‐based HIV protease inhibitors

Symmetric fluoro‐substituted diol‐based HIV protease inhibitors

Improved Structure−Activity Relationship Analysis of HIV-1 Protease Inhibitors Using Interaction Kinetic Data

Progress in the Discovery of BACE Inhibitors

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Product

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Design and Synthesis of PotentC₂-Symmetric Diol-Based HIV-1 Protease Inhibitors: Effects of Fluoro Substitution