Studies on Orally Available Inhibitors of HIV Protease. Peptidyl Aldehydes and Trifluoromethyl Ketones

Hodge, C. Nicholas; Aldrich, Paul E.; Otto, M. J.; Rayner, Marlene M.; Wong, Y. Nancy; Erickson‐Viitanen, Susan

doi:10.1177/095632029400500407

Cited by 12 publications

(5 citation statements)

References 30 publications

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“…110 Better oral bioavailability can be achieved by low-molecular-weight peptidyl aldehyde inhibitors of HIV protease. 171 As an alternative to the peptide-based approach, penicillin-derived compounds have been pursued as HIV protease inhibitors, i.e. penicillin C2 symmetric dimers held together by an ethylenediamine linker (46),172 and monomeric penicillins linked to peptide isosteres such as statine.…”

Section: Protease Inhibitorsmentioning

confidence: 99%

Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention with HIV Infections

Clercq¹

1995

J. Med. Chem.

713

425

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Section: Protease Inhibitorsmentioning

confidence: 99%

Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention with HIV Infections

Clercq¹

1995

J. Med. Chem.

713

425

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“…31 Peptide inhibitors that inhibit primarily the longer and potentially more pathologically relevant 1-42 form of Aβ have yet to be reported. Since aldehydes and difluoro ketones are known to inhibit a variety of proteases including serine, cysteine, and aspartic acid proteases, [32][33][34][35] it is not known to which of these protease classes γ-secretase belongs.…”

Section: Introductionmentioning

confidence: 99%

A Combinatorial Approach to the Identification of Dipeptide Aldehyde Inhibitors of β-Amyloid Production

Higaki¹,

Chakravarty²,

Bryant³

et al. 1999

J. Med. Chem.

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In an effort to rapidly identify potent inhibitors of Abeta production and to probe the amino acid sequence specificity of the protease(s) responsible for the production of this peptide, a large number of dipeptide aldehydes were combinatorially synthesized and manually evaluated for their inhibitory properties. The starting point for this study was the dipeptide aldehyde carbobenzoxyl-valinyl-phenylalanal previously shown to inhibit the production of Abeta in CHO cells stably transfected with the cDNA encoding betaAPP695. Pools of related dipeptide aldehydes were combinatorially synthesized, and the most active pool was deconvoluted, resulting in the identification of the most active inhibitor of this pool. Systematic optimization of this inhibitor resulted in a series of dipeptide aldehydes with enhanced potencies relative to carbobenzoxyl-valinyl-phenylalanal. The most active dipeptide aldehydes were those that possessed hydrophobic amino acids at both the P1 and P2 positions. The most potent compound identified in this study was 3, 5-dimethoxycinnamamide-isoleucinyl-leucinal with an IC(50) of 9.6 microM, approximately 10-fold more active than carbobenzoxyl-valinyl-phenylalanal. In immunoprecipitation experiments using antibodies directed toward either Abeta1-40 or Abeta1-42, 3,5-dimethoxycinnamamide-isoleucinyl-leucinal, like carbobenzoxyl-valinyl-phenylalanal, preferentially inhibited the shorter 1-40 form of Abeta, whereas the longer 1-42 form was not as strongly inhibited. These results suggest that dipeptide aldehydes related to carbobenzoxyl-valinyl-phenylalanal inhibit Abeta through similar mechanisms and demonstrate the utility of a combinatorial synthesis approach to rapidly identify potent inhibitors of Abeta production.

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“…We wished to compare these relatively small inhibitors, which provide side-chain functionalities that fill the S2, Si, Si', and S2' subsites of the enzyme, with some of the most potent inhibitors described in the literature to date. These peptidelike inhibitors include the C2-symmetrical diol Q8024 (12,13), the hydroxypropylene isostere A-80987 (16,17), and the hydroxyethylimine isostere Ro-31-8959. (32).…”

mentioning

confidence: 99%

Potency and selectivity of inhibition of human immunodeficiency virus protease by a small nonpeptide cyclic urea, DMP 323

Erickson‐Viitanen

Klabe

Cawood

et al. 1994

Antimicrob Agents Chemother

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DMP 323 is a potent inhibitor of the protease of human immunodeficiency virus (HIV), with antiviral activity against both HIV type 1 and HIV type 2. This compound is representative of a class of small, novel, nonpeptide cyclic urea inhibitors of HIV protease that were designed on the basis of three-dimensional structural information and three-dimensional database searching. We report here studies of the kinetics of DMP 323 inhibition of the cleavage of peptide and HIV-1 gag polyprotein substrates. DMP 323 acts as a rapidly binding, competitive inhibitor of HIV protease. DMP 323 is as potent against both peptide and viral polyprotein substrates as A-80987, Q8024, and Ro-31-8959, which are among the most potent inhibitors of HIV protease described in the literature to date. Incubation with human plasma or serum did not decrease the effective potency of DMP 323 for HIV protease, suggesting that plasma protein binding is of a low aflinity relative to that of HIV protease. DMP 323 was also assessed for its ability to inhibit the mammalian proteases renin, pepsin, cathepsin D, cathepsin G, and chymotrypsin. No inhibition of greater than 12% was observed for any of these enzymes at concentrations of DMP 323 that were 350 to 40,000 times higher than that required to inhibit the viral protease 50%o.

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Studies on Orally Available Inhibitors of HIV Protease. Peptidyl Aldehydes and Trifluoromethyl Ketones

Cited by 12 publications

References 30 publications

Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention with HIV Infections

Toward Improved Anti-HIV Chemotherapy: Therapeutic Strategies for Intervention with HIV Infections

A Combinatorial Approach to the Identification of Dipeptide Aldehyde Inhibitors of β-Amyloid Production

Potency and selectivity of inhibition of human immunodeficiency virus protease by a small nonpeptide cyclic urea, DMP 323

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