2. Academic Validation
  3. Identification of Novel Series of Potent and Selective Relaxin Family Peptide Receptor 1 (RXFP1) Agonists

Identification of Novel Series of Potent and Selective Relaxin Family Peptide Receptor 1 (RXFP1) Agonists

  • J Med Chem. 2024 Mar 28;67(6):4442-4462. doi: 10.1021/acs.jmedchem.3c02183.
Kenneth L Granberg 1,  Shigeki Sakamaki 2,  Ryuichi Fuchigami 2,  Yasuki Niwa 2,  Masakazu Fujio 2,  Harutoshi Kato 2,  Fredrik Bergström 3,  Niklas Larsson 4,  Mikael Persson 5,  Inmaculada C Villar 6,  Takuya Fujita 2,  Emiko Sugikawa 2,  Magnus Althage 7,  Naoko Yano 2,  Yoshito Yokoyama 2,  Junpei Kimura 2,  Mark Lal 8,  Hideki Mochida 2
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal 43183, Sweden.
  • 2 Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
  • 3 Drug Metabolism and Pharmacokinetics (DMPK), Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal 431 83, Sweden.
  • 4 Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Mölndal 431 83, Sweden.
  • 5 Cardiovascular, Renal and Metabolism Safety, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Gothenburg, Mölndal 431 83, Sweden.
  • 6 Regulatory Toxicology & Safety Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
  • 7 Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal 431 83, Sweden.
  • 8 Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), Biopharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal 431 83, Sweden.
PMID: 38502780 DOI: 10.1021/acs.jmedchem.3c02183
Abstract

Relaxin H2 is a clinically relevant peptide agonist for relaxin family peptide receptor 1 (RXFP1), but a combination of this hormone's short plasma half-life and the need for injectable delivery limits its therapeutic potential. We sought to overcome these limitations through the development of a potent small molecule (SM) RXFP1 agonist. Although two large SM HTS campaigns failed in identifying suitable hit series, we uncovered novel chemical space starting from the only known SM RXFP1 agonist series, represented by ML290. Following a design-make-test-analyze strategy based on improving early dose to man ranking, we discovered compound 42 (AZ7976), a highly selective RXFP1 agonist with sub-nanomolar potency. We used AZ7976, its 10 000-fold less potent enantiomer 43 and recombinant relaxin H2 to evaluate in vivo pharmacology and demonstrate that AZ7976-mediated heart rate increase in rats was a result of RXFP1 agonism. As a result, AZ7976 was selected as lead for continued optimization.

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