title: Design, synthesis and optimization of bis-amide derivatives as CSF1R inhibitors.
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.
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Sreekanth A
authors.initials: SA
authors.lastname: Ramachandran
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Pradeep S
authors.initials: PS
authors.lastname: Jadhavar
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Sandeep K
authors.initials: SK
authors.lastname: Miglani
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Manvendra P
authors.initials: MP
authors.lastname: Singh
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Deepak P
authors.initials: DP
authors.lastname: Kalane
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Agarwal
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Balaji D
authors.initials: BD
authors.lastname: Sathe
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Kakoli
authors.initials: K
authors.lastname: Mukherjee
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Ashu
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Srijan
authors.initials: S
authors.lastname: Haldar
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Mohd
authors.initials: M
authors.lastname: Raja
authors.affiliation: Integral BioSciences Pvt. Ltd, C-64, Hosiery Complex Phase II Extension, Noida, Uttar Pradesh 201306, India.
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Singh
authors.affiliation: Medivation, now Pfizer, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
authors.forename: Son M
authors.initials: SM
authors.lastname: Pham
authors.affiliation: Medivation, now Pfizer, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
authors.forename: Sarvajit
authors.initials: S
authors.lastname: Chakravarty
authors.affiliation: Medivation, now Pfizer, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Quinn
authors.affiliation: Fundación Ciencia y Vida, Avenida Zañartu 1482, Ñuñoa, Santiago 778027, Chile.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Belmar
authors.affiliation: Fundación Ciencia y Vida, Avenida Zañartu 1482, Ñuñoa, Santiago 778027, Chile.
authors.forename: Ivan E
authors.initials: IE
authors.lastname: Alfaro
authors.affiliation: Schrödinger, Inc., 120 West 45th Street, 17th Floor, New York, NY 10036, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Higgs
authors.affiliation: Medivation, now Pfizer, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bernales
authors.affiliation: Medivation, now Pfizer, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Herrera
authors.affiliation: Medivation, now Pfizer, 525 Market Street, 36th Floor, San Francisco, CA 94105, USA. Electronic address: roopa.rai@hotmail.com.
authors.forename: Roopa
authors.initials: R
authors.lastname: Rai
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D001665:Binding Sites; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D015195:Drug Design; D006207:Half-Life; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D000067996:RAW 264.7 Cells; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Bis-amides; CSF1R; FMS; Inhibitors