Biphenylsulfonyl-thiophene-carboxamidine inhibitors of the complement component C1s.
Complement activation has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury, acute respiratory distress syndrome, and acute transplant rejection. Even though the complement cascade provides several protein targets for potential therapeutic intervention only two complement inhibitors have been approved so far for clinical use including anti-C5 antibodies for the treatment of paroxysmal nocturnal hemoglobinuria and purified C1-esterase inhibitor replacement therapy for the control of hereditary angioedema flares. In the present study, optimization of potency and physicochemical properties of a series of thiophene amidine-based C1s inhibitors with potential utility as intravenous agents for the inhibition of the classical pathway of complement is described.
Travins
Jeremy M
JM
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 665 Stockton Drive, Exton, PA 19341, USA.
Ali
Farah
F
Huang
Hui
H
Ballentine
Shelley K
SK
Khalil
Ehab
E
Hufnagel
Heather R
HR
Pan
Wenxi
W
Gushue
Joan
J
Leonard
Kristi
K
Bone
Roger F
RF
Soll
Richard M
RM
DesJarlais
Renee L
RL
Crysler
Carl S
CS
Ninan
Nisha
N
Kirkpatrick
Jennifer
J
Cummings
Maxwell D
MD
Huebert
Norman
N
Molloy
Christopher J
CJ
Gaul
Michael
M
Tomczuk
Bruce E
BE
Subasinghe
Nalin L
NL
D000818:Animals; D001665:Binding Sites; D003173:Complement C1s / Q000037:antagonists & inhibitors*; D006207:Half-Life; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
D006571:Heterocyclic Compounds; D003173:Complement C1s