2. Academic Validation
  3. Discovery of a Chiral 2,4-Substituted Pyrrolo[2,3- d]pyrimidine as a Potent, Selective, and Orally Bioavailable LRRK2 Inhibitor

Discovery of a Chiral 2,4-Substituted Pyrrolo[2,3- d]pyrimidine as a Potent, Selective, and Orally Bioavailable LRRK2 Inhibitor

  • J Med Chem. 2025 May 22;68(10):9926-9946. doi: 10.1021/acs.jmedchem.4c02473.
Omar Moukha-Chafiq 1,  Tuyana Malankhanova 2,  Jacob Valiyaveettil 1,  Vandana Gupta 1,  Hollis Kezar 1,  Sixue Zhang 1 3,  Theresa H Nguyen 1,  Shuklendu Karyakarte 1,  Wei Zhang 1,  Soumendranath Bhakat 3,  Robert A Galemmo 1,  Subramaniam Ananthan 1,  Anna Manuvakhova 1,  Larry I Ross 1,  Joseph A Maddry 1,  Robert Bostwick 1,  Mark J Suto 1,  Andrew West 2,  Corinne E Augelli-Szafran 1
Affiliations

Affiliations

  • 1 Scientific Platforms Division, Southern Research, Birmingham, Alabama 35205, United States.
  • 2 Department of Pharmacology, Duke University School of Medicine, Durham, North Carolina 27710, United States.
  • 3 System Pharmacology AI Research Center, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35233, United States.
PMID: 40353293 DOI: 10.1021/acs.jmedchem.4c02473
Abstract

Inhibition of leucine-rich repeat kinase (LRRK2) activity with small molecules has emerged as a potential novel therapeutic target for Parkinson's disease (PD). We have previously reported the identification of SRI-29132 as a potent LRRK2 Inhibitor, but the presence of a 6-thioether moiety, which is an oxidative liability, precludes its further development. Herein, we report another hit-to-lead optimization study that led to the discovery of the chiral 2,4-substituted pyrrolo[2,3-d]pyrimidine series as potent LRRK2 inhibitors. Our lead analog 6, derived from a high-throughput screening hit SRI-31255, exhibits excellent LRRK2 inhibition activity and, high selectivity across the kinome. Further, the molecule has acceptable absorption, distribution, metabolism, and excretion (ADME), and pharmacokinetic (PK) properties, as well as brain permeability and no off-target liabilities. This new class of compounds serves as a novel series for further study in the development of LRRK2 inhibitors for therapy.

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