2. Academic Validation
  3. Spirocyclopentane as a Novel Scaffold for Potent Ghrelin Receptor Full Agonists

Spirocyclopentane as a Novel Scaffold for Potent Ghrelin Receptor Full Agonists

  • J Med Chem. 2025 Dec 25;68(24):26061-26084. doi: 10.1021/acs.jmedchem.5c02097.
Cristina Gardelli 1,  Antonio Llinas 2,  Igor Shamovsky 3,  Yao Xiong 4,  Rongfeng Chen 4,  Moya Caffrey 3,  Lotta Hidestål 3,  Asim Ray 3,  Martin Cooper 3,  Tina Jellesmark Jensen 5,  Leif Hultin 6,  Ulf Andersson 6,  Sara Lundqvist 7,  Botilda Lindberg 8,  Helena Douglasson 8,  Nina Krutrök 9,  Anna Pettersen 10,  Richard Lewis 3,  Paul Jansson 1
Affiliations

Affiliations

  • 1 Projects Department, Respiratory and Immunology, R&D BioPharmaceuticals, AstraZeneca, Mölndal SE-43183, Sweden.
  • 2 DMPK Department, Respiratory and Immunology, R&D BioPharmaceuticals, AstraZeneca, Mölndal SE-43183, Sweden.
  • 3 Medicinal Chemistry Department, Respiratory and Immunology, R&D BioPharmaceuticals, AstraZeneca, Mölndal SE-43183, Sweden.
  • 4 Department of Medicinal Chemistry, Pharmaron Beijing, Co., Ltd., Beijing 100176, China.
  • 5 Early Clinical Development, Respiratory and Immunology, R&D BioPharmaceuticals, AstraZeneca, Mölndal SE-43183, Sweden.
  • 6 Clinical Pharmacology & Safety Sciences, R&D BioPharmaceuticals, AstraZeneca, Mölndal SE-43183, Sweden.
  • 7 Discovery Sciences, R&D BioPharmaceuticals, AstraZeneca, Mölndal SE-43183, Sweden.
  • 8 Bioscience, Respiratory and Immunology, R&D BioPharmaceuticals, AstraZeneca, Mölndal SE-43183, Sweden.
  • 9 Bioscience Cardiovascular Department, Research & Early Development, Cardiovascular, Renal & Metabolism, R&D BioPharmaceuticals, AstraZeneca, Mölndal SE-43183, Sweden.
  • 10 Pharmaceutical Sciences, R&D BioPharmaceuticals, AstraZeneca, Mölndal SE-43183, Sweden.
PMID: 41347768 DOI: 10.1021/acs.jmedchem.5c02097
Abstract

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 22 suitable for progression as a clinical candidate.

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