Design and synthesis of diaminopyrrolidinone inhibitors of human osteoclast cathepsin K

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 14, 1999, Pages 1907-1910

  Duffy, Kevin J ^a   Ridgers, Lance H ^a   Desjarlais, Renee L ^a   Tomaszek, Thaddeus A ^a   Bossard, Mary J ^a   Thompson, Scott K ^a   Keenan, Richard M ^a   Veber, Daniel F ^a  

^a GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

2 PYRROLIDONE DERIVATIVE; CATHEPSIN K; DIAMINOPYRROLIDINONE; UNCLASSIFIED DRUG;

ARTICLE; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG STRUCTURE; DRUG SYNTHESIS; OSTEOCLAST; OSTEOLYSIS; PROTEIN DEGRADATION; X RAY CRYSTALLOGRAPHY;

AMINES; CATHEPSINS; CRYSTALLOGRAPHY, X-RAY; CYSTEINE PROTEINASE INHIBITORS; DRUG DESIGN; HUMANS; MODELS, MOLECULAR; OSTEOCLASTS; PEPTIDES; PYRROLIDINONES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0033584188     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00322-4     Document Type: Article

References (18)

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9. The synthesis and biological properties of lactam constrained peptide isosteres have been studied (e.g., Freidinger, R. M.; Schwenk; Perlow, D.; Veber, D. F. J. Org. Chem. 1982, 47, 104), however the corresponding azapeptide analogues have not been investigated to the best of our knowledge.
10. The synthesis of (3S)-3-tritylamino-1-tert-butoxycarbonylaminopyrrolidin-2-one has been reported; Barlos, K.; Papaioannou, D.; Voliotis, S. Justus Liebigs Ann. Chem. 1988, 1127.
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13. 2O requires: %C, 59.2, %H, 5.8, %N, 11.9; found %C, 59.1, %H, 5.8, %N, 11.5.
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15. The conversion in the reprotection step was low resulting in the poor isolated yield of 16. Acylation of the intermediate primary amine with aryl carboxylic acids typically progresses in >80% yield (studies will be published elsewhere).
16. 6S requires: %C, 62.3; %H, 6.5; %N, 11.0; found %C, 62.0; %H, 6.5; %N, 10.8.
17. Thereby providing good evidence that the stereochemistry at the quaternary center is as predicted.
18. Recently Roush et al. (Bioorg. Med .chem. 1998, 6, 2477) investigated the inhibition of various cysteine proteases by conformationally-contrained peptidomimetics such as the lactam-constrained analogue of Cbz-Phe-Phe-CHO aldehyde shown below (17). Their results showed that inclusion of the pyrrolidinone ring can reduce dramatically the inhibition of certain cysteine proteases (e.g., cruzain) presumably due to unfavourable steric interactions while it's presence is tolerated for other proteases, in this case the Leishmania major protease (which likely have more relaxed steric requirements at the position where the pyrrolidinone is introduced). The results presented in this letter fall within the latter category. (Formula presented)