Azepanone-based inhibitors of human cathepsin L.
The extension of a previously reported cathepsin K azepanone-based inhibitor template to the design and synthesis of potent and selective inhibitors of the homologous cysteine protease cathepsin L is detailed. Structure-activity studies examining the effect of inhibitor selectivity as a function of the P3 and P2 binding elements of the potent cathepsin K inhibitor 1 revealed that incorporation of either a P3 quinoline-8-carboxamide or a naphthylene-1-carboxamide led to increased selectivity for cathepsin L over cathepsin K. Substitution of the P2 leucine of 1 with either a phenylalanine or a beta-naphthylalanine also resulted in an increased selectivity for cathepsin L over cathepsin K. Molecular modeling studies with the inhibitors docked within the active sites of both cathepsins L and K have rationalized the observed selectivities. Optimization of cathepsin L binding by the combination of the P3 naphthylene-1-carboxamide with the P2 beta-naphthylalanine provided 15, which is a potent, selective, and competitive inhibitor of human cathepsin L with a K(i) = 0.43 nM.
Marquis
Robert W
RW
Department of Medicinal Chemistry, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA. Robert.W.Marquis@gsk.com
James
Ian
I
Zeng
Jin
J
Trout
Robert E Lee
RE
Thompson
Scott
S
Rahman
Attiq
A
Yamashita
Dennis S
DS
Xie
Ren
R
Ru
Yu
Y
Gress
Catherine J
CJ
Blake
Simon
S
Lark
Michael A
MA
Hwang
Shing-Mei
SM
Tomaszek
Thaddeus
T
Offen
Priscilla
P
Head
Martha S
MS
Cummings
Maxwell D
MD
Veber
Daniel F
DF
D000577:Amides / Q000737:chemistry; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D011804:Quinolines / Q000737:chemistry; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry
D000577:Amides; D001381:Azepines; D015853:Cysteine Proteinase Inhibitors; D011804:Quinolines; D013450:Sulfones; C506290:naphthalene-2-carboxylic acid (2-naphthalen-2-yl-1-(3-oxo-1-(pyridine-2-sulfonyl)azepan-4-ylcarbamoyl)ethyl)amide; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L