Core Replacements in a Potent Series of VEGFR-2 Inhibitors and Their Impact on Potency, Solubility, and hERG.
Anti-VEGF therapy has been a clinically validated treatment of age-related macular degeneration (AMD). We have recently reported the discovery of indole based oral VEGFR-2 inhibitors that provide sustained ocular retention and efficacy in models of wet-AMD. We disclose herein the synthesis and the biological evaluation of a series of novel core replacements as an expansion of the reported indole based VEGFR-2 inhibitor series. Addition of heteroatoms to the existing core and/or rearranging the heteroatoms around the 6-5 bicyclic ring structure produced a series of compounds that generally retained good on-target potency and an improved solubility profile. The hERG affinity was proven not be dependent on the change in lipophilicity through alteration of the core structure. A serendipitous discovery led to the identification of a new indole-pyrimidine connectivity: from 5-hydroxy to 6-hydroxyindole with potentially vast implication on the in vitro/in vivo properties of this class of compounds.
Global Discovery Chemistry, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
Nello
N
Mainolfi
Global Discovery Chemistry, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
James
J
Powers
Global Discovery Chemistry, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
Erik
E
Meredith
Global Discovery Chemistry, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
Jason
J
Elliott
Global Discovery Chemistry, Novartis Institutes for Biomedical Research , 100 Technology Square, Cambridge, Massachusetts 02139, United States.
Karl G
KG
Gunderson
Ophthalmology, Novartis Institutes for Biomedical Research , 500 Technology Square, Cambridge, Massachusetts 02139, United States.
Stephen
S
Poor
Ophthalmology, Novartis Institutes for Biomedical Research , 500 Technology Square, Cambridge, Massachusetts 02139, United States.
Fang
F
Liu
Ophthalmology, Novartis Institutes for Biomedical Research , 500 Technology Square, Cambridge, Massachusetts 02139, United States.
Karen
K
Anderson
AMD; KDR; VEGF; Vascular endothelial growth factor receptor 2; bicyclic core; scaffold morphing