title: Ligand efficient tetrahydro-pyrazolopyridines as inhibitors of ERK2 kinase.
abstract: A series of structure based drug design hypotheses and focused screening efforts drove improvements in the potency and lipophilic efficiency of tetrahydro-pyrazolopyridine based ERK2 inhibitors. Elaboration of a fragment chemical lead established a new lipophilic aryl-Tyr interaction resulting in a substantial potency improvement. Subsequent cleavage of the lipophilic moiety led to reconfiguration of the ligand bound binding cleft. The reconfiguration established a polar contact between a newly liberated N-H and a vicinal Asp, resulting in further improvements in lipophilic efficiency and in vitro clearance.
authors.affiliation: Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Ave., Cambridge, MA 02139, USA. Electronic address: jeffrey.bagdanoff@novartis.com.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Bagdanoff
authors.affiliation: Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for BioMedical Research, 4560 Horton St., Building 4, Emeryville, CA 94608, USA.
authors.forename: Rama
authors.initials: R
authors.lastname: Jain
authors.affiliation: Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for BioMedical Research, 4560 Horton St., Building 4, Emeryville, CA 94608, USA.
authors.forename: Wooseok
authors.initials: W
authors.lastname: Han
authors.affiliation: Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for BioMedical Research, 4560 Horton St., Building 4, Emeryville, CA 94608, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Poon
authors.affiliation: Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for BioMedical Research, 4560 Horton St., Building 4, Emeryville, CA 94608, USA.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Lee
authors.affiliation: Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for BioMedical Research, 4560 Horton St., Building 4, Emeryville, CA 94608, USA.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Bellamacina
authors.affiliation: Global Discovery Chemistry/Oncology and Exploratory Chemistry, Novartis Institutes for BioMedical Research, 4560 Horton St., Building 4, Emeryville, CA 94608, USA.
authors.forename: Mika
authors.initials: M
authors.lastname: Lindvall
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine; D001224:Aspartic Acid; D000255:Adenosine Triphosphate; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1
keywords: ATP binding cleft; ERK2 kinase; Extraction ratio; Fragment lead; Structure based drug design