TY - JOUR
T1 - Synthesis and evaluation of analogs of 5′-(((Z)-4-amino-2-butenyl)methylamino)-5′-deoxyadenosine (MDL 73811, or AbeAdo) – An inhibitor of S-adenosylmethionine decarboxylase with antitrypanosomal activity
AU - Brockway, Anthony J.
AU - Volkov, Oleg A.
AU - Cosner, Casey C.
AU - MacMillan, Karen S.
AU - Wring, Stephen A.
AU - Richardson, Thomas E.
AU - Peel, Michael
AU - Phillips, Margaret A.
AU - De Brabander, Jef K.
N1 - Publisher Copyright:
© 2017 Elsevier Ltd
PY - 2017
Y1 - 2017
N2 - We describe our efforts to improve the pharmacokinetic properties of a mechanism-based suicide inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (AdoMetDC), essential for the survival of the eukaryotic parasite Trypanosoma brucei responsible for Human African Trypanosomiasis (HAT). The lead compound, 5′-(((Z)-4-amino-2-butenyl)methylamino)-5′-deoxyadenosine (1, also known as MDL 73811, or AbeAdo), has curative efficacy at a low dosage in a hemolymphatic model of HAT but displayed no demonstrable effect in a mouse model of the CNS stage of HAT due to poor blood–brain barrier permeation. Therefore, we prepared and evaluated an extensive set of analogs with modifications in the aminobutenyl side chain, the 5′-amine, the ribose, and the purine fragments. Although we gained valuable structure–activity insights from this comprehensive dataset, we did not gain traction on improving the prospects for CNS penetration while retaining the potent antiparasitic activity and metabolic stability of the lead compound 1.
AB - We describe our efforts to improve the pharmacokinetic properties of a mechanism-based suicide inhibitor of the polyamine biosynthetic enzyme S-adenosylmethionine decarboxylase (AdoMetDC), essential for the survival of the eukaryotic parasite Trypanosoma brucei responsible for Human African Trypanosomiasis (HAT). The lead compound, 5′-(((Z)-4-amino-2-butenyl)methylamino)-5′-deoxyadenosine (1, also known as MDL 73811, or AbeAdo), has curative efficacy at a low dosage in a hemolymphatic model of HAT but displayed no demonstrable effect in a mouse model of the CNS stage of HAT due to poor blood–brain barrier permeation. Therefore, we prepared and evaluated an extensive set of analogs with modifications in the aminobutenyl side chain, the 5′-amine, the ribose, and the purine fragments. Although we gained valuable structure–activity insights from this comprehensive dataset, we did not gain traction on improving the prospects for CNS penetration while retaining the potent antiparasitic activity and metabolic stability of the lead compound 1.
KW - Antitrypanosomal
KW - Human African Trypanosomiasis
KW - Metabolism
KW - Permeability
KW - S-adenosylmethionine decarboxylase
KW - Structure-activity relationship
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U2 - 10.1016/j.bmc.2017.07.063
DO - 10.1016/j.bmc.2017.07.063
M3 - Article
C2 - 28807574
AN - SCOPUS:85028334051
SN - 0968-0896
VL - 25
SP - 5433
EP - 5440
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 20
ER -