title: Rapid development of piperidine carboxamides as potent and selective anaplastic lymphoma kinase inhibitors.
abstract: Piperidine carboxamide 1 was identified as a novel inhibitor of anaplastic lymphoma kinase (ALK enzyme assay IC(50) = 0.174 μM) during high throughput screening, with selectivity over the related kinase insulin-like growth factor-1 (IGF1R). The X-ray cocrystal structure of 1 with the ALK kinase domain revealed an unusual DFG-shifted conformation, allowing access to an extended hydrophobic pocket. Structure-activity relationship (SAR) studies were focused on the rapid parallel optimization of both the right- and left-hand side of the molecule, culminating in molecules with improved potency and selectivity over IGF1R.
authors.affiliation: Medicinal Chemistry Research Technologies, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Marian C
authors.initials: MC
authors.lastname: Bryan
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Doherty
authors.forename: James R
authors.initials: JR
authors.lastname: Falsey
authors.forename: Alan C
authors.initials: AC
authors.lastname: Cheng
authors.forename: Renee
authors.initials: R
authors.lastname: Emkey
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Brake
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lewis
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D031541:Fluorescence Resonance Energy Transfer; D057166:High-Throughput Screening Assays; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; C572353:N-(3-(4-morpholinyl)benzyl)-1-(2-((3,4,5-trimethoxyphenyl)amino)-4-pyrimidinyl)-3-piperidinecarboxamide; D010880:Piperidines; D011743:Pyrimidines; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1