2024
DOI: 10.1021/acs.jmedchem.3c02183
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Identification of Novel Series of Potent and Selective Relaxin Family Peptide Receptor 1 (RXFP1) Agonists

Kenneth L. Granberg,
Shigeki Sakamaki,
Ryuichi Fuchigami
et al.

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, represen… Show more

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Cited by 5 publications
(12 citation statements)
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“…We have previously shown by using radioligand binding experiments that SM RXFP1 agonists (e.g., AZ7976) do not compete with but rather enhance 125 I-relaxin H2 binding to RXFP1, suggesting distinct binding sites for relaxin and SM agonists on the receptor . This prompted us to perform positive allosteric modulator (PAM) experiments using cAMP assays to determine any potential functional interplay between relaxin H2 and either 6 , AZ7976, or ML290.…”
Section: Resultssupporting
confidence: 79%
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“…We have previously shown by using radioligand binding experiments that SM RXFP1 agonists (e.g., AZ7976) do not compete with but rather enhance 125 I-relaxin H2 binding to RXFP1, suggesting distinct binding sites for relaxin and SM agonists on the receptor . This prompted us to perform positive allosteric modulator (PAM) experiments using cAMP assays to determine any potential functional interplay between relaxin H2 and either 6 , AZ7976, or ML290.…”
Section: Resultssupporting
confidence: 79%
“…In broad human off target panels (Table ), both 6 and 7 showed a favorable selectivity profile with few hits up to 10 μM. As previously reported for AZ7976 and its enantiomer, the targets hit by either 6 or 7 showed an overlap and the largest difference was seen for the significantly more potent binding of 7 to TSPO. Finally, both 6 and 7 were tested against the phylogenetically closest leucine-rich repeat-containing subgroup of class A human GPCRs (LGR4, LGR5, LGR6, LSHR (LHCGR), FSHR, TSHR and RXFP2) at Discovery X in concentration response, agonist mode up to 100 μM without any noticeable agonistic activity (selectivity for hRXFP1 > 7 600-fold).…”
Section: Resultsmentioning
confidence: 98%
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