Small Molecule CD38 Inhibitors: Synthesis of 8-Amino- N 1-inosine 5'-monophosphate, Analogues and Early Structure-Activity Relationship

Although a monoclonal antibody targeting the multifunctional ectoenzyme CD38 is an FDA-approved drug, few small molecule inhibitors exist for this enzyme that catalyzes inter alia the formation and metabolism of the 1-ribosylated, Ca -mobilizing, second messenger cyclic adenosine 5'-diphosphori...

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Bibliographic Details
Published inMolecules (Basel, Switzerland) Vol. 26; no. 23
Main Authors Watt, Joanna M, Graeff, Richard, Potter, Barry V L
Format Journal Article
LanguageEnglish
Published Switzerland 26.11.2021
Subjects
Adenosine Diphosphate Ribose - metabolism
ADP-ribosyl Cyclase 1 - antagonists & inhibitors
ADP-ribosyl Cyclase 1 - metabolism
Calcium - metabolism
Catalysis - drug effects
Cyclic ADP-Ribose - metabolism
Humans
Hydrolysis - drug effects
Inosine - metabolism
Inosine Monophosphate - chemistry
Small Molecule Libraries - chemistry
Small Molecule Libraries - pharmacology
Structure-Activity Relationship
synthesis
fragment
nucleotide
cADPR
cyclase
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Summary:Although a monoclonal antibody targeting the multifunctional ectoenzyme CD38 is an FDA-approved drug, few small molecule inhibitors exist for this enzyme that catalyzes inter alia the formation and metabolism of the 1-ribosylated, Ca -mobilizing, second messenger cyclic adenosine 5'-diphosphoribose (cADPR). 1-Inosine 5'-monophosphate ( 1-IMP) is a fragment directly related to cADPR. 8-Substituted- 1-IMP derivatives, prepared by degradation of cyclic parent compounds, inhibit CD38-mediated cADPR hydrolysis more efficiently than related cyclic analogues, making them attractive for inhibitor development. We report a total synthesis of the 1-IMP scaffold from adenine and a small initial compound series that facilitated early delineation of structure-activity parameters, with analogues evaluated for inhibition of CD38-mediated hydrolysis of cADPR. The 5'-phosphate group proved essential for useful activity, but substitution of this group by a sulfonamide bioisostere was not fruitful. 8-NH - 1-IMP is the most potent inhibitor (IC = 7.6 μM) and importantly HPLC studies showed this ligand to be cleaved at high CD38 concentrations, confirming its access to the CD38 catalytic machinery and demonstrating the potential of our fragment approach.
ISSN:1420-3049