Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties.
Compound 2 was previously identified as a potent inhibitor of factor XIa lacking oral bioavailability. A structure-based approach was used to design analogs of 2 with novel P1 moieties with good selectivity profiles and oral bioavailability. Further optimization of the P1 group led to the identification of a 4-chlorophenyltetrazole P1 analog, which when combined with further modifications to the linker and P2' group provided compound 32 with FXIa Ki=6.7 nM and modest oral exposure in dogs.
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States. Electronic address: donald.pinto@bms.com.
Donald J P
DJ
Pinto
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States. Electronic address: joanne.smallheer@bms.com.
Joanne M
JM
Smallheer
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States.
James R
JR
Corte
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States.
Erin J D
EJ
Austin
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States.
Cailan
C
Wang
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States.
Tianan
T
Fang
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States.
Leon M
LM
Smith
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States.
Karen A
KA
Rossi
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States.
Alan R
AR
Rendina
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States.
Jeffrey M
JM
Bozarth
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States.
Ge
G
Zhang
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States.
Anzhi
A
Wei
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States.
Vidhyashankar
V
Ramamurthy
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States.
Steven
S
Sheriff
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States.
Joseph E
JE
Myers
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States.
Paul E
PE
Morin
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States.
Joseph M
JM
Luettgen
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States.
Dietmar A
DA
Seiffert
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States.
Mimi L
ML
Quan
Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States.
Ruth R
RR
Wexler
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015945:Factor XIa / Q000037:antagonists & inhibitors* / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007191:Indazoles; D015945:Factor XIa
Anticoagulant; Bioavailability; Factor XIa; Serine protease; Thrombosis