Asymmetric Synthesis of CIDD-0072424 via an Enantioselective Nitro-Mannich Reaction: A Central Nervous System Penetrant, Selective Small Molecule Inhibitor of Protein Kinase C Epsilon

  • J Org Chem. 2024 Apr 5;89(7):5134-5141. doi: 10.1021/acs.joc.3c02917.
Harmannus De Kraker  1 ,  Hua-Yu Leo Wang  1 ,  Hadi D Arman  1 ,  Rachel N Renteria  1 ,  Caleb N Fleischer  2 ,  Robert O Messing  2 ,  Stanton F McHardy  1
Affiliations
  • 1. Center for Innovative Drug Discovery, Department of Chemistry, University of Texas San Antonio, San Antonio, Texas 78254, United States.
  • 2. College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, United States.
PMID: 38489762 DOI: 10.1021/acs.joc.3c02917
Abstract

CIDD-0072424 is a novel small molecule developed in silico with remarkable activity for the inhibition of protein kinase C (PKC)-epsilon to treat alcohol use disorder. We developed a concise synthesis of (S)-2 that is highly enantioselective, scalable, and amenable for 3-point structure-activity relationship (SAR) studies for compound optimization. The highly enantioselective nitro-Mannich reaction was achieved through a dual-reagent catalysis system. The overall utility and the efficiency of the enantioselective route provided a scalable synthesis of both PKCε inhibitors 1 and 2.

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