Discovery of potent & selective inhibitors of activated thrombin-activatable fibrinolysis inhibitor for the treatment of thrombosis.
Thrombin-activatable fibrinolysis inhibitor (TAFI) has emerged as a key link between the coagulation and fibrinolysis cascades and represents a promising new target for the treatment of thrombosis. A novel series of imidazolepropionic acids has been designed that exhibit high potency against activated TAFI (TAFIa) and excellent selectivity over plasma carboxypeptidase N (CPN). Structure activity relationships suggest that the imidazole moiety plays a key role in binding to the catalytic zinc of TAFIa, and this has been supported by crystallographic studies using porcine pancreatic carboxypeptidase B as a surrogate for TAFIa. The SAR program led to the identification of 21 (TAFIa Ki = 10 nM, selectivity TAFIa/CPN > 1000) as a candidate for clinical development. Compound 21 exhibited antithrombotic efficacy in a rabbit model of venous thrombosis, yet had no effect on surgical bleeding in the rabbit. In addition, 21 exhibited an excellent preclinical and clinical pharmacokinetic profile, characterized by paracellular absorption, low clearance, and a low volume of distribution, fully consistent with its physicochemical properties of low molecular weight (MW = 239) and high hydrophilicity (log D = -2.8). These data indicate 21 (UK-396,082) has potential as a novel TAFIa inhibitor for the treatment of thrombosis and other fibrin-dependent diseases in humans.
Bunnage
Mark E
ME
Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Kent, U.K. mark.bunnage@pfizer.com
Blagg
Julian
J
Steele
John
J
Owen
Dafydd R
DR
Allerton
Charlotte
C
McElroy
Andrew B
AB
Miller
Duncan
D
Ringer
Tracy
T
Butcher
Ken
K
Beaumont
Kevin
K
Evans
Karen
K
Gray
Andrew J
AJ
Holland
Stephen J
SJ
Feeder
Neil
N
Moore
Robert S
RS
Brown
David G
DG
D000596:Amino Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D016063:Blood Loss, Surgical / Q000517:prevention & control; D043424:Carboxypeptidase B / Q000737:chemistry; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004285:Dogs; D005342:Fibrinolysis / Q000187:drug effects*; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D010179:Pancreas / Q000201:enzymology; D011817:Rabbits; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine; D013917:Thrombin / Q000378:metabolism*; D054556:Venous Thromboembolism / Q000188:drug therapy
C526817:5-amino-2-((1-n-propyl-1H-imidazol-4-yl)methyl)pentanoic acid; D000596:Amino Acids; D005343:Fibrinolytic Agents; D007093:Imidazoles; D043424:Carboxypeptidase B; D013917:Thrombin