title: Pharmacokinetic optimitzation of CCG-203971: Novel inhibitors of the Rho/MRTF/SRF transcriptional pathway as potential antifibrotic therapeutics for systemic scleroderma.
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.
authors.affiliation: Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Hutchings
authors.affiliation: Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Erika M
authors.initials: EM
authors.lastname: Lisabeth
authors.affiliation: Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Walajapet
authors.initials: W
authors.lastname: Rajeswaran
authors.affiliation: Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Wilson
authors.affiliation: Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Sorenson
authors.affiliation: Department of Internal Medicine, Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
authors.forename: Phillip L
authors.initials: PL
authors.lastname: Campbell
authors.affiliation: Department of Internal Medicine, Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Ruth
authors.affiliation: Department of Internal Medicine, Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
authors.forename: Asif
authors.initials: A
authors.lastname: Amin
authors.affiliation: Department of Internal Medicine, Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
authors.forename: Pei-Suen
authors.initials: PS
authors.lastname: Tsou
authors.affiliation: Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Leipprandt
authors.affiliation: Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Olson
authors.affiliation: UM Pharmacokinetics Core, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Wen
authors.affiliation: UM Pharmacokinetics Core, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: UM Pharmacokinetics Core, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Internal Medicine, Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Khanna
authors.affiliation: Department of Internal Medicine, Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Fox
authors.affiliation: Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI 48824, USA.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Neubig
authors.affiliation: Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: sdlarsen@med.umich.edu.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Larsen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009557:Nipecotic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D012234:Rho Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D027602:Serum Response Element / Q000187:drug effects; D012867:Skin / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: C431575:MRTFA protein, human; C000589288:N-(4-chlorophenyl)-1-((3-(furan-2-yl)phenyl)carbonyl)piperidine-3-carboxamide; D009557:Nipecotic Acids; D012234:Rho Factor; D015534:Trans-Activators
keywords: Antifibrotic; Fibrosis; MRTF; Myofibroblast; Rho; Scleroderma