Azepanone-based inhibitors of human and rat cathepsin K

被引:114
作者
Marquis, RW
Ru, Y
LoCastro, SM
Zeng, J
Yamashita, DS
Oh, HJ
Erhard, KF
Davis, LD
Tomaszek, TA
Tew, D
Salyers, K
Proksch, J
Ward, K
Smith, B
Levy, M
Cummings, MD
Haltiwanger, RC
Trescher, G
Wang, B
Hemling, ME
Quinn, CJ
Cheng, HY
Lin, F
Smith, WW
Janson, CA
Zhao, BG
McQueney, MS
D'Alessio, K
Lee, CP
Marzulli, A
Dodds, RA
Blake, S
Hwang, SM
James, IE
Gress, CJ
Bradley, BR
Lark, MW
Gowen, M
Veber, DF
机构
[1] Glaxo SmithKline, Dept Med Chem, King Of Prussia, PA 19406 USA
[2] Glaxo SmithKline, Dept Mech Enzymol, King Of Prussia, PA 19406 USA
[3] Glaxo SmithKline, Dept Drug Metab & Pharmacokinet, King Of Prussia, PA 19406 USA
[4] Glaxo SmithKline, Dept Phys & Struct Chem, King Of Prussia, PA 19406 USA
[5] Glaxo SmithKline, Dept Biol Struct, King Of Prussia, PA 19406 USA
[6] Glaxo SmithKline, Dept Prot Biochem, King Of Prussia, PA 19406 USA
[7] Glaxo SmithKline, Dept Life Cycle Management & Drug Delivery Syst, King Of Prussia, PA 19406 USA
[8] Glaxo SmithKline, Dept Bone & Cartilage Biol, King Of Prussia, PA 19406 USA
关键词
D O I
10.1021/jm000481x
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The synthesis, in vitro activities, and pharmacokinetics of a series of azepanone-based inhibitors of the cysteine protease cathepsin K (EC 3.4.22.38) are described. These compounds show improved configurational stability of the C-4 diastereomeric center relative to the previously published five- and six-membered ring ketone-based inhibitor series. Studies in this series have led to the identification of 20, a potent, selective inhibitor of human cathepsin K (K-i = 0.16 nM) as well as 24, a potent inhibitor of both human (K-i = 0.0048 nM) and rat (K-i,K-app = 4.8 nM) cathepsin K. Small-molecule X-ray crystallographic analysis of 20 established the C-4 S stereochemistry as being critical for potent inhibition and that unbound 20 adopted the expected equatorial conformation for the C-4 substituent. Molecular modeling studies predicted the higher energy axial orientation at C-4 of 20 when bound within the active site of cathepsin K, a feature subsequently confirmed by X-ray crystallography. Pharmacokinetic studies in the rat show 20 to be 42% orally bioavailable. Comparison of the transport of the cyclic and acyclic analogues through CaCo-2 cells suggests that oral bioavailability of the acyclic derivatives is limited by a P-glycoprotein-mediated efflux mechanism. It is concluded that the introduction of a conformational constraint has served the dual purpose of increasing inhibitor potency by locking in a bioactive conformation as well as locking out available conformations which may serve as substrates for enzyme systems that limit oral bioavailability.
引用
收藏
页码:1380 / 1395
页数:16
相关论文
共 66 条
[1]   STEREOCONTROLLED SYNTHESIS OF ERYTHRO N-PROTECTED ALPHA-AMINO EPOXIDES AND PEPTIDYL EPOXIDES [J].
ALBECK, A ;
PERSKY, R .
TETRAHEDRON, 1994, 50 (21) :6333-6346
[2]   STEREOCHEMISTRY, A BASIS FOR SOPHISTICATED NONSENSE IN PHARMACOKINETICS AND CLINICAL-PHARMACOLOGY [J].
ARIENS, EJ .
EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, 1984, 26 (06) :663-668
[3]  
BAYLEY H, 1978, TETRAHEDRON LETT, P3633
[4]   Intestinal drug metabolism and antitransport processes: A potential paradigm shift in oral drug delivery [J].
Benet, LZ ;
Wu, CY ;
Hebert, MF ;
Wacher, VJ .
JOURNAL OF CONTROLLED RELEASE, 1996, 39 (2-3) :139-143
[5]   Proteolytic activity of human osteoclast cathepsin K - Expression, purification, activation, and substrate identification [J].
Bossard, MJ ;
Tomaszek, TA ;
Thompson, SK ;
Amegadzie, BY ;
Hanning, CR ;
Jones, C ;
Kurdyla, JT ;
McNulty, DE ;
Drake, FH ;
Gowen, M ;
Levy, MA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1996, 271 (21) :12517-12524
[6]   HUMAN CATHEPSIN O2, A NOVEL CYSTEINE PROTEASE HIGHLY EXPRESSED IN OSTEOCLASTOMAS AND OVARY MOLECULAR-CLONING, SEQUENCING AND TISSUE DISTRIBUTION [J].
BROMME, D ;
OKAMOTO, K .
BIOLOGICAL CHEMISTRY HOPPE-SEYLER, 1995, 376 (06) :379-384
[7]  
Chan OH, 1996, DRUG DISCOV TODAY, V1, P461
[8]   THE INFLUENCE OF PEPTIDE STRUCTURE ON TRANSPORT ACROSS CACO-2 CELLS .2. PEPTIDE-BOND MODIFICATION WHICH RESULTS IN IMPROVED PERMEABILITY [J].
CONRADI, RA ;
HILGERS, AR ;
HO, NFH ;
BURTON, PS .
PHARMACEUTICAL RESEARCH, 1992, 9 (03) :435-439
[9]   NITRILE OXIDES IN MEDICINAL CHEMISTRY .2. SYNTHESIS OF THE 2 ENANTIOMERS OF DIHYDROMUSCIMOL [J].
DEAMICI, M ;
DEMICHELI, C ;
MISANI, V .
TETRAHEDRON, 1990, 46 (06) :1975-1986
[10]   Use of X-ray co-crystal structures and molecular modeling to design potent and selective non-peptide inhibitors of cathepsin K [J].
DesJarlais, RL ;
Yamashita, DS ;
Oh, HJ ;
Uzinskas, IN ;
Erhard, KF ;
Allen, AC ;
Haltiwanger, RC ;
Zhao, BG ;
Smith, WW ;
Abdel-Meguid, SS ;
D'Alessio, K ;
Janson, CA ;
McQueney, MS ;
Tomaszek, TA ;
Levy, MA ;
Veber, DF .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1998, 120 (35) :9114-9115