title: 2-(1H-Imidazol-4-yl)ethanamine and 2-(1H-pyrazol-1-yl)ethanamine side chain variants of the IGF-1R inhibitor BMS-536924.
abstract: A series of IGF-1R inhibitors is disclosed, wherein the (m-chlorophenyl)ethanol side chain of BMS-536924 (1) is replaced with a series of 2-(1H-imidazol-4-yl)ethanamine and 2-(1H-pyrazol-1-yl)ethanamine side chains. Some analogs show improved IGF-1R potency and oral exposure. Analogs from both series, 16a and 17f, show in vivo activity comparable to 1 in our constitutively activated IGF-1R Sal tumor model. This may be the due to the improved protein binding in human and mouse serum for imidazole 16a and the excellent oral exposure of pyrazole 17f.
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. Mark.Saulnier@bms.com
authors.forename: Mark G
authors.initials: MG
authors.lastname: Saulnier
authors.forename: David B
authors.initials: DB
authors.lastname: Frennesson
authors.forename: Mark D
authors.initials: MD
authors.lastname: Wittman
authors.forename: Kurt
authors.initials: K
authors.lastname: Zimmermann
authors.forename: Upender
authors.initials: U
authors.lastname: Velaparthi
authors.forename: David R
authors.initials: DR
authors.lastname: Langley
authors.forename: Charles
authors.initials: C
authors.lastname: Struzynski
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Sang
authors.forename: Joan
authors.initials: J
authors.lastname: Carboni
authors.forename: Aixin
authors.initials: A
authors.lastname: Li
authors.forename: Ann
authors.initials: A
authors.lastname: Greer
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Praveen
authors.initials: P
authors.lastname: Balimane
authors.forename: Marco
authors.initials: M
authors.lastname: Gottardis
authors.forename: Ricardo
authors.initials: R
authors.lastname: Attar
authors.forename: Dolatrai
authors.initials: D
authors.lastname: Vyas
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011485:Protein Binding; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D044967:Serum; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C504983:BMS 536924; D001562:Benzimidazoles; D011728:Pyridones; D017526:Receptor, IGF Type 1