Document Report Card

ID: ALA1130170

Journal: J Med Chem

Title: Orally active trifluoromethyl ketone inhibitors of human leukocyte elastase.

Authors: Veale CA, Bernstein PR, Bohnert CM, Brown FJ, Bryant C, Damewood JR, Earley R, Feeney SW, Edwards PD, Gomes B, Hulsizer JM, Kosmider BJ, Krell RD, Moore G, Salcedo TW, Shaw A, Silberstein DS, Steelman GB, Stein M, Strimpler A, Thomas RM, Vacek EP, Williams JC, Wolanin DJ, Woolson S.

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.

CiteXplore: 9379436

DOI: 10.1021/jm970250z