2. Academic Validation
  3. Design, synthesis and optimization of bis-amide derivatives as CSF1R inhibitors

Design, synthesis and optimization of bis-amide derivatives as CSF1R inhibitors

  • Bioorg Med Chem Lett. 2017 May 15;27(10):2153-2160. doi: 10.1016/j.bmcl.2017.03.064.
Sreekanth A Ramachandran 1,  Pradeep S Jadhavar 1,  Sandeep K Miglani 1,  Manvendra P Singh 1,  Deepak P Kalane 1,  Anil K Agarwal 1,  Balaji D Sathe 1,  Kakoli Mukherjee 1,  Ashu Gupta 1,  Srijan Haldar 1,  Mohd Raja 1,  Siddhartha Singh 1,  Son M Pham 2,  Sarvajit Chakravarty 2,  Kevin Quinn 2,  Sebastian Belmar 3,  Ivan E Alfaro 3,  Christopher Higgs 4,  Sebastian Bernales 2,  Francisco J Herrera 2,  Roopa Rai 5
Affiliations

Affiliations

  • 1 Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
  • 2 Medivation, now Pfizer, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
  • 3 Fundación Ciencia y Vida, Avenida Zañartu 1482, Ñuñoa, Santiago 778027, Chile.
  • 4 Schrödinger, Inc., 120 West 45th Street, 17th Floor, New York, NY 10036, USA.
  • 5 Medivation, now Pfizer, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA. Electronic address: roopa.rai@hotmail.com.
PMID: 28377059 DOI: 10.1016/j.bmcl.2017.03.064
Abstract

Signaling via the receptor tyrosine kinase CSF1R is thought to play an important role in recruitment and differentiation of tumor-associated macrophages (TAMs). TAMs play pro-tumorigenic roles, including the suppression of anti-tumor immune response, promotion of angiogenesis and tumor cell metastasis. Because of the role of this signaling pathway in the tumor microenvironment, several small molecule CSF1R kinase inhibitors are undergoing clinical evaluation for Cancer therapy, either as a single agent or in combination with other Cancer therapies, including immune checkpoint inhibitors. Herein we describe our lead optimization effort that resulted in the identification of a potent, cellular active and orally bioavailable bis-amide CSF1R inhibitor. Docking and biochemical analysis allowed the removal of a metabolically labile and poorly permeable methyl piperazine group from an early lead compound. Optimization led to improved metabolic stability and Caco2 permeability, which in turn resulted in good oral bioavailability in mice.

Keywords

Bis-amides; CSF1R; FMS; Inhibitors.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-101774
    98.11%, c-Fms 抑制剂
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