AMP deaminase inhibitors. 3. SAR of 3-(carboxyarylalkyl)coformycin aglycon analogues.
N3-Substituted coformycin aglycon analogues with improved AMP deaminase (AMPDA) inhibitory potency are described. Replacement of the 5-carboxypentyl substituent in the lead AMPDA inhibitor 3-(5-carboxypentyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1, 3]diazepin-8-ol (2) described in the previous article with various carboxyarylalkyl groups resulted in compounds with 10-100-fold improved AMPDA inhibitory potencies. The optimal N3 substituent had m-carboxyphenyl with a two-carbon alkyl tether. For example, 3-[2-(3-carboxy-5-ethylphenyl)ethyl]-3,6,7,8-tetrahydroimidazo[4, 5-d][1,3]diazepin-8-ol (43g) inhibited human AMPDA with a K(i) = 0. 06 microM. The compounds within the series also exhibited >1000-fold specificity for AMPDA relative to adenosine deaminase.
Kasibhatla
S R
SR
Metabasis Therapeutics Inc., 9390 Towne Centre Drive, San Diego, California 92121, USA. rao@mbasis.com
Bookser
B C
BC
Probst
G
G
Appleman
J R
JR
Erion
M D
MD
D000659:AMP Deaminase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry; D003070:Coformycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
C407510:3-(2-(3-carboxy-5-ethylphenyl)ethyl)-3,6,7,8-tetrahydroimidazo(4,5-d)(1,3)diazepin-8-ol; D001381:Azepines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D003070:Coformycin; D000659:AMP Deaminase