2. Academic Validation
  3. Discovery of the Novel, Orally Active, and Selective LPA1 Receptor Antagonist ACT-1016-0707 as a Preclinical Candidate for the Treatment of Fibrotic Diseases

Discovery of the Novel, Orally Active, and Selective LPA1 Receptor Antagonist ACT-1016-0707 as a Preclinical Candidate for the Treatment of Fibrotic Diseases

  • J Med Chem. 2024 Feb 22;67(4):2397-2424. doi: 10.1021/acs.jmedchem.3c01827.
Cyrille Lescop 1,  Magdalena Birker 2,  Christine Brotschi 1,  Cédric Bürki 3,  Keith Morrison 4,  Sylvie Froidevaux 4,  Stéphane Delahaye 5,  Oliver Nayler 2,  Martin H Bolli 1
Affiliations

Affiliations

  • 1 DD Chemistry, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland.
  • 2 DD Biology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland.
  • 3 Chemistry Process R&D, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland.
  • 4 DD Pharmacology, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland.
  • 5 Preclinical DMPK, Idorsia Pharmaceuticals, Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland.
PMID: 38349250 DOI: 10.1021/acs.jmedchem.3c01827
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 accumulated in the liver. In vitro studies indicated that 17 is an organic anion co-transporting polypeptide 1B1 (OATP1B1) substrate. Although analogue 24 was no longer a substrate of OATP1B1, PK studies suggested that the compound undergoes enterohepatic recirculation. Replacing the carboxylic acidic side chain by a non-acidic sulfamide moiety and further fine-tuning of the scaffold yielded the potent, orally active LPAR1 Antagonist 49, which was selected for preclinical development for the treatment of fibrotic diseases.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z