2024
DOI: 10.1021/acs.jmedchem.3c01827
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Discovery of the Novel, Orally Active, and Selective LPA1 Receptor Antagonist ACT-1016-0707 as a Preclinical Candidate for the Treatment of Fibrotic Diseases

Cyrille Lescop,
Magdalena Birker,
Christine Brotschi
et al.

Abstract: Piperidine 3 is a potent and selective lysophosphatidic acid receptor subtype 1 receptor (LPAR1) antagonist that has shown efficacy in a skin vascular leakage target engagement model in mice. However, compound 3 has very high human plasma protein binding and high clearance in rats, which could significantly hamper its clinical development. Continued lead optimization led to the potent, less protein bound, metabolically stable, and orally active azetidine 17. Rat pharmacokinetics (PK) studies revealed that 17 a… Show more

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Cited by 2 publications
(1 citation statement)
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“…While the acid present in 18 helped fine-tune the molecule’s physicochemical and DMPK profile, compound 18 showed very high plasma protein binding and high clearance in RLM, prompting us to consider further optimization efforts. The unique scaffold described in this report opens new avenues toward the discovery of additional novel LPAR1 antagonists that may serve as candidates for clinical development …”
Section: Discussionmentioning
confidence: 99%
“…While the acid present in 18 helped fine-tune the molecule’s physicochemical and DMPK profile, compound 18 showed very high plasma protein binding and high clearance in RLM, prompting us to consider further optimization efforts. The unique scaffold described in this report opens new avenues toward the discovery of additional novel LPAR1 antagonists that may serve as candidates for clinical development …”
Section: Discussionmentioning
confidence: 99%