Design and synthesis of polyethylene glycol-modified biphenylsulfonyl-thiophene-carboxamidine inhibitors of the complement component C1s.
Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties.
Janssen Pharmaceutical Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA. NSUBASIN@its.jnj.com
Nalin L
NL
Subasinghe
Ehab
E
Khalil
Jeremy M
JM
Travins
Farah
F
Ali
Shelley K
SK
Ballentine
Heather R
HR
Hufnagel
Wenxi
W
Pan
Kristi
K
Leonard
Roger F
RF
Bone
Richard M
RM
Soll
Carl S
CS
Crysler
Nisha
N
Ninan
Jennifer
J
Kirkpatrick
Michael X
MX
Kolpak
Karen A
KA
Diloreto
Stephen H
SH
Eisennagel
Norman D
ND
Huebert
Christopher J
CJ
Molloy
Bruce E
BE
Tomczuk
Michael D
MD
Gaul
D000577:Amides / Q000737:chemistry*; D000818:Animals; D003173:Complement C1s / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D006207:Half-Life; D011092:Polyethylene Glycols / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D013876:Thiophenes / Q000737:chemistry*
D000577:Amides; D011480:Protease Inhibitors; D013876:Thiophenes; D011092:Polyethylene Glycols; D003173:Complement C1s