Spirocyclopentane as a Novel Scaffold for Potent Ghrelin Receptor Full Agonists
Muscle atrophy and cachexia are common comorbidities among patients suffering from cancer, chronic obstructive pulmonary disease, acquired immunodeficiency syndrome, and several other chronic diseases. The peptide hormone ghrelin exerts pleiotropic effects; it acts by stimulating growth hormone secretion and subsequent increase of insulin-like growth factor-1 levels, an important mediator of muscle growth and repair. Ghrelin also acts on inflammation, appetite, and adipogenesis and, therefore, has been considered a promising therapeutic target for catabolic conditions. We previously reported on the synthesis and properties of indane- and pyrrolidine-based series of ghrelin receptor full agonists, which led to a sustained increase of insulin-like growth factor-1 in a dog pharmacodynamic study. Herein, we report a subsequent lead optimization work that, taking advantage of the previous work on indanes and pyrrolidines, with the synthesis of only two dozen compounds, brought to the identification of compound <b>22</b> suitable for progression as a clinical candidate.
Authors
- Yao Xiong (ORCID: https://orcid.org/0000-0001-9350-6112)
- Anna Pettersen (ORCID: https://orcid.org/0000-0002-0025-7936)
- Moya Caffrey
- Helena Douglasson
- Nina Krutrök (ORCID: https://orcid.org/0000-0001-6745-2368)
- Tina Jellesmark Jensen
- Botilda Lindberg
- Igor L. Shamovsky (ORCID: https://orcid.org/0000-0002-2881-9531)
- Rongfeng Chen (ORCID: https://orcid.org/0000-0002-6704-8530)
- Richard J. Lewis (ORCID: https://orcid.org/0000-0001-9404-8520)
- Sara Lundqvist (ORCID: https://orcid.org/0000-0001-9717-8347)
- Antonio Llinàs (ORCID: https://orcid.org/0000-0003-4620-9363)
- Cristina Gardelli (ORCID: https://orcid.org/0000-0003-1169-2180)
- Jan Andersson (ORCID: https://orcid.org/0000-0003-0316-3860)
- Asim K. Ray (ORCID: https://orcid.org/0000-0002-5392-0041)
- Lotta Hidestål
- Martin Cooper (ORCID: https://orcid.org/0009-0006-8925-5940)
- Leif Hultin
- Paul Jansson
Institutions
- Bioscience Research (US)
- Pharmaron (United Kingdom) (GB)
- AstraZeneca (Australia) (AU)
- AstraZeneca (Switzerland) (CH)
- Institute of Immunology (HR)
- Respiratory Clinical Trials (AU)
- BioScience Laboratories (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-12-05
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02097
- Primary Topic
- Regulation of Appetite and Obesity
- Type
- article
- Field-Weighted Citation Impact
- 0.00