AMP deaminase inhibitors. 5. Design, synthesis, and SAR of a highly potent inhibitor series.
A highly potent AMP deaminase (AMPDA) inhibitor series was discovered by replacing the N3 substitutents of the two lead AMPDA inhibitor series with a conformationally restricted group. The most potent compound, 3-[2-(3-carboxy-4-bromo-5,6,7,8-tetrahydronaphthyl)ethyl]-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol (24b), represents a 10- to 250-fold enhancement in AMPDA inhibitory potency without loss in the enzyme specificity. The potency of the inhibitor 24b (AMPDA K(i) = 0.002 microM) is 10(5)-fold lower than the Km for the substrate AMP. It represents the most potent nonnucleotide AMPDA inhibitor known.
Kasibhatla
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Metabasis Therapeutics Inc., 9390 Towne Centre Drive, San Diego, California 92121, USA. rao@mbasis.com
Bookser
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Xiao
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Erion
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D000659:AMP Deaminase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000243:Adenosine Deaminase / Q000737:chemistry; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry; D002417:Cattle; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
C421743:3-(2-(3-carboxy-4-bromo-5,6,7,8-tetrahydronaphthyl)ethyl)-3,6,7,8-tetrahydroimidazo(4,5-d)(1,3)diazepin-8-ol; D058892:Adenosine Deaminase Inhibitors; D001381:Azepines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D000243:Adenosine Deaminase; D000659:AMP Deaminase