Discovery of MK-1468: A Potent, Kinome-Selective, Brain-Penetrant Amidoisoquinoline LRRK2 Inhibitor for the Potential Treatment of Parkinson's Disease

  • J Med Chem. 2023 Oct 20. doi: 10.1021/acs.jmedchem.3c01486.
Solomon D Kattar  1 ,  Anmol Gulati  1 ,  Kaila A Margrey  1 ,  Mitchell H Keylor  1 ,  Michael Ardolino  1 ,  Xin Yan  1 ,  Rebecca Johnson  1 ,  Rachel L Palte  1 ,  Spencer E McMinn  1 ,  Lisa Nogle  1 ,  Jing Su  1 ,  Dong Xiao  1 ,  Jennifer Piesvaux  1 ,  Susi Lee  2 ,  Laxminarayan G Hegde  1 ,  Janice D Woodhouse  1 ,  Robert Faltus  1 ,  Lily Y Moy  1 ,  Tina Xiong  1 ,  Paul J Ciaccio  1 ,  Kara Pearson  3 ,  Mayankbhai Patel  1 ,  Karin M Otte  1 ,  Cheryl E G Leyns  1 ,  Matthew E Kennedy  1 ,  David Jonathan Bennett  1 ,  Erin F DiMauro  1 ,  Matthew J Fell  1 ,  Peter H Fuller  1
Affiliations
  • 1. Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
  • 2. Merck & Co., Inc., 126 E. Lincoln Ave., Rahway, New Jersey 07065, United States.
  • 3. Merck & Co., Inc., 770 Sumneytown Pike., West Point, Pennsylvania 19486, United States.
PMID: 37861679 DOI: 10.1021/acs.jmedchem.3c01486
Abstract

Genetic mutation of the leucine-rich repeat kinase 2 (LRRK2) protein has been associated with Parkinson's Disease (PD), a disabling and progressive neurodegenerative disorder that is devoid of efficacious disease-modifying therapies. Herein, we describe the invention of an amidoisoquinoline (IQ)-derived LRRK2 inhibitor lead chemical series. Knowledge-, structure-, and property-based drug design in concert with rigorous application of in silico calculations and presynthesis predictions enabled the prioritization of molecules with favorable CNS "drug-like" physicochemical properties. This resulted in the discovery of compound 8, which was profiled extensively before human ether-a-go-go (hERG) ion channel inhibition halted its progression. Strategic reduction of lipophilicity and basicity resulted in attenuation of hERG ion channel inhibition while maintaining a favorable CNS efflux transporter profile. Further structure- and property-based optimizations resulted in the discovery of preclinical candidate MK-1468. This exquisitely selective LRRK2 inhibitor has a projected human dose of 48 mg BID and a preclinical safety profile that supported advancement toward GLP toxicology studies.

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