Synthesis and P1' SAR exploration of potent macrocyclic tissue factor-factor VIIa inhibitors.
Selective tissue factor-factor VIIa complex (TF-FVIIa) inhibitors are viewed as promising compounds for treating thrombotic disease. In this contribution, we describe multifaceted exploratory SAR studies of S1'-binding moieties within a macrocyclic chemotype aimed at replacing cyclopropyl sulfone P1' group. Over the course of the optimization efforts, the 1-(1H-tetrazol-5-yl)cyclopropane P1' substituent emerged as an improved alternative, offering increased metabolic stability and lower clearance, while maintaining excellent potency and selectivity.
Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, United States. Electronic address: vladimir.ladziata@bms.com.
Vladimir Uladzimir
VU
Ladziata
Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, United States.
Peter W
PW
Glunz
Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, United States.
Yan
Y
Zou
Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, United States.
Xiaojun
X
Zhang
Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, United States.
Wen
W
Jiang
Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, United States.
Swanee
S
Jacutin-Porte
Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, United States.
Daniel L
DL
Cheney
Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, United States.
Anzhi
A
Wei
Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, United States.
Joseph M
JM
Luettgen
Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, United States.
Timothy M
TM
Harper
Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, United States.
Pancras C
PC
Wong
Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, United States.
Dietmar
D
Seiffert
Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, United States.
Ruth R
RR
Wexler
Bristol-Myers Squibb Research & Development, Princeton, NJ 08543, United States.
E Scott
ES
Priestley
D000818:Animals; D004285:Dogs; D015195:Drug Design; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013925:Thromboplastin / Q000037:antagonists & inhibitors*
D047028:Macrocyclic Compounds; D013925:Thromboplastin; D015942:Factor VIIa
Anticoagulant; Factor VIIa-TF inhibitor; Macrocycle; Thrombosis