New alpha-substituted succinate-based hydroxamic acids as TNFalpha convertase inhibitors.
Tumor necrosis factor alpha convertase (TACE), the enzyme responsible for the processing of pro-TNFalpha to TNFalpha, has been reported to be a metalloproteinase closely related to matrix metalloproteinases (MMPs). Current inhibitors of TACE such as succinate-based hydroxamic acids exemplified by Marimastat (TACE IC(50): 3.8 nM; blood IC(50): 7 microM) and BB1101 (TACE IC(50): 0.2 nM; blood IC(50): 2.3 microM) suffer from modest potency in blood and poor in vivo properties. The introduction of new bulky alpha-substituents into these succinate-based hydroxamic acids was studied. Substituents such as thioethers, sulfonamides, and ethers showed improved potency against TACE when compared with Marimastat. Although this improvement did not translate into better blood potency for thioether or ether substituents, the sulfonamide series exhibited improved potency both against TACE and in blood when compared with Marimastat. Optimization of this sulfonamide series has culminated in the identification of heterocyclic bicyclic sulfonamides such as 3t (TACE IC(50): 0.57 nM; blood IC(50): 0.28 microM).
Barlaam
B
B
AstraZeneca, Zeneca Pharma, Centre de Recherches, Z.I. La Pompelle, BP1050, 51689 Reims Cedex 2, France.
Bird
T G
TG
Lambert-Van Der Brempt
C
C
Campbell
D
D
Foster
S J
SJ
Maciewicz
R
R
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000284:Administration, Oral; D000818:Animals; D002144:Callithrix; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000097:blood; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013386:Succinates / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
D006877:Hydroxamic Acids; C401329:N(2)-(4-(N-hydroxyamino)-2-isobutyl-3-(4-oxo-3,4-dihydroquinazoline-6-sulfonylamino)succinyl)-tert-leucine-N(1)-methylamide; D011480:Protease Inhibitors; D011799:Quinazolines; D013386:Succinates; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human