2. Academic Validation
  3. Pharmacokinetic optimitzation of CCG-203971: Novel inhibitors of the Rho/MRTF/SRF transcriptional pathway as potential antifibrotic therapeutics for systemic scleroderma

Pharmacokinetic optimitzation of CCG-203971: Novel inhibitors of the Rho/MRTF/SRF transcriptional pathway as potential antifibrotic therapeutics for systemic scleroderma

  • Bioorg Med Chem Lett. 2017 Apr 15;27(8):1744-1749. doi: 10.1016/j.bmcl.2017.02.070.
Kim M Hutchings 1,  Erika M Lisabeth 2,  Walajapet Rajeswaran 1,  Michael W Wilson 1,  Roderick J Sorenson 1,  Phillip L Campbell 3,  Jeffrey H Ruth 3,  Asif Amin 3,  Pei-Suen Tsou 3,  Jeffrey R Leipprandt 2,  Samuel R Olson 2,  Bo Wen 4,  Ting Zhao 4,  Duxin Sun 4,  Dinesh Khanna 3,  David A Fox 3,  Richard R Neubig 2,  Scott D Larsen 5
Affiliations

Affiliations

  • 1 Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
  • 2 Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI 48824, USA.
  • 3 Department of Internal Medicine, Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
  • 4 UM Pharmacokinetics Core, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
  • 5 Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: [email protected].
PMID: 28285914 DOI: 10.1016/j.bmcl.2017.02.070
Abstract

We recently reported the development of a novel inhibitor of Rho-mediated gene transcription (1, CCG-203971) that is efficacious in multiple animal models of acute fibrosis, including scleroderma, when given intraperitoneally. The modest in vivo potency and poor pharmacokinetics (PK) of this lead, however, make it unsuitable for long term efficacy studies. We therefore undertook a systematic medicinal chemistry effort to improve both the metabolic stability and the solubility of 1, resulting in the identification of two analogs achieving over 10-fold increases in plasma exposures in mice. We subsequently showed that one of these analogs (8f, CCG-232601) could inhibit the development of bleomycin-induced dermal fibrosis in mice when administered orally at 50mg/kg, an effect that was comparable to what we had observed earlier with 1 at a 4-fold higher IP dose.

Keywords

Antifibrotic; Fibrosis; MRTF; Myofibroblast; Rho; Scleroderma.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-111432
    Rho/MRTF/SRF Inhibitor
    Ras