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Bioorg Med Chem. 2014 Apr 1;22(7):2261-8. doi: 10.1016/j.bmc.2014.02.010. Epub 2014 Feb 18.

Design and synthesis of conformationally restricted inhibitors of active thrombin activatable fibrinolysis inhibitor (TAFIa).

Author information

1
Cardiovascular and Metabolic Disorders Research Area, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden.
2
Cardiovascular and Metabolic Disorders Research Area, AstraZeneca R&D Mölndal, SE-431 83 Mölndal, Sweden. Electronic address: magnus.polla@astrazeneca.com.

Abstract

A series of 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid and 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylic acid derivatives designed as inhibitors of TAFIa has been prepared via a common hydrogenation-alkylation sequence starting from the appropriate benzimidazole and imidazopyridine system. We present a successful design strategy using a conformational restriction approach resulting in potent and selective inhibitors of TAFIa. The X-ray structure of compound 5 in complex with a H333Y/H335Q double mutant TAFI indicate that the conformational restriction is responsible for the observed potency increase.

KEYWORDS:

AstraZeneca; Carboxypeptidase U; Conformational restriction; Imidazole; Rigidification; TAFIa

PMID:
24588961
DOI:
10.1016/j.bmc.2014.02.010
[Indexed for MEDLINE]

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