title: Biphenylsulfonyl-thiophene-carboxamidine inhibitors of the complement component C1s.
abstract: 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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 665 Stockton Drive, Exton, PA 19341, USA.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Travins
authors.forename: Farah
authors.initials: F
authors.lastname: Ali
authors.forename: Hui
authors.initials: H
authors.lastname: Huang
authors.forename: Shelley K
authors.initials: SK
authors.lastname: Ballentine
authors.forename: Ehab
authors.initials: E
authors.lastname: Khalil
authors.forename: Heather R
authors.initials: HR
authors.lastname: Hufnagel
authors.forename: Wenxi
authors.initials: W
authors.lastname: Pan
authors.forename: Joan
authors.initials: J
authors.lastname: Gushue
authors.forename: Kristi
authors.initials: K
authors.lastname: Leonard
authors.forename: Roger F
authors.initials: RF
authors.lastname: Bone
authors.forename: Richard M
authors.initials: RM
authors.lastname: Soll
authors.forename: Renee L
authors.initials: RL
authors.lastname: DesJarlais
authors.forename: Carl S
authors.initials: CS
authors.lastname: Crysler
authors.forename: Nisha
authors.initials: N
authors.lastname: Ninan
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kirkpatrick
authors.forename: Maxwell D
authors.initials: MD
authors.lastname: Cummings
authors.forename: Norman
authors.initials: N
authors.lastname: Huebert
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Molloy
authors.forename: Michael
authors.initials: M
authors.lastname: Gaul
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Tomczuk
authors.forename: Nalin L
authors.initials: NL
authors.lastname: Subasinghe
mesh_terms: 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
chemical_list: D006571:Heterocyclic Compounds; D003173:Complement C1s