2. Academic Validation
  3. Orally active trifluoromethyl ketone inhibitors of human leukocyte elastase

Orally active trifluoromethyl ketone inhibitors of human leukocyte elastase

  • J Med Chem. 1997 Sep 26;40(20):3173-81. doi: 10.1021/jm970250z.
C A Veale 1,  P R Bernstein,  C M Bohnert,  F J Brown,  C Bryant,  J R Damewood Jr,  R Earley,  S W Feeney,  P D Edwards,  B Gomes,  J M Hulsizer,  B J Kosmider,  R D Krell,  G Moore,  T W Salcedo,  A Shaw,  D S Silberstein,  G B Steelman,  M Stein,  A Strimpler,  R M Thomas,  E P Vacek,  J C Williams,  D J Wolanin,  S Woolson
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, ZENECA Pharmaceuticals, A Business Unit of ZENECA Inc., Wilmington, Delaware 19897, USA.
PMID: 9379436 DOI: 10.1021/jm970250z
Abstract

This paper describes the development a series of peptidyl trifluoromethyl ketone inhibitors of human leukocyte Elastase which are found to have excellent pharmacological profiles. Methods have been developed that allow for the synthesis of these inhibitors in stereochemically pure form. Two of these compounds, 1k and 1l, have high levels of oral bioavailability in several species. Compound 1l has entered development as ZD8321 and is presently undergoing clinical evaluation. These compounds demonstrate that peptidyl trifluoromethyl ketone inhibitors can achieve high levels of oral activity and bioavailability, and therefore they may prove useful as therapeutic agents in the treatment of diseases in which Elastase is implicated.

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