Discovery of a Novel Class of Imidazo[1,2-a]Pyridines with Potent PDGFR Activity and Oral Bioavailability

Abstract

The in silico construction of a PDGFRβ kinase homology model and ensuing medicinal chemistry guided by molecular modeling, led to the identification of potent, small molecule inhibitors of PDGFR. Subsequent exploration of structure-activity relationships (SAR) led to the incorporation of a constrained secondary amine to enhance selectivity. Further refinements led to the integration of a fluorine substituted piperidine, which resulted in significant reduction of P-glycoprotein (Pgp) mediated efflux and improved bioavailability. Compound 28 displayed oral exposure in rodents and had a pronounced effect in a pharmacokinetic-pharmacodynamic (PKPD) assay.

Revealing the Macromolecular Targets of Fragment‐Like Natural Products

“…Interestingly,i somacroin is as ubstructure of the recently reported single-digit nanomolar and micromolar inhibitors for PDGFRb [22] and IKKb, [23] respectively,t hus further supporting the prevalidation of NP-derived molecular architectures,the suitability of NP fragments as leads for development and, in this specific case,t he molecular binding hypothesis probed with 2. Interestingly,i somacroin is as ubstructure of the recently reported single-digit nanomolar and micromolar inhibitors for PDGFRb [22] and IKKb, [23] respectively,t hus further supporting the prevalidation of NP-derived molecular architectures,the suitability of NP fragments as leads for development and, in this specific case,t he molecular binding hypothesis probed with 2.…”

“…We further probed the molecular basis of PDGFR kinase inhibition by synthesizing analogue 2.F rom the sharply decreased inhibitory potencyo f2 at 150 mm (3 %a nd 10 % inhibition of PDGFRa and b,respectively), our data suggest directed interactions of the imidazole moiety in isomacroin with the kinase hinge-binding motif of both PDGFR isoforms. Interestingly,i somacroin is as ubstructure of the recently reported single-digit nanomolar and micromolar inhibitors for PDGFRb [22] and IKKb, [23] respectively,t hus further supporting the prevalidation of NP-derived molecular architectures,the suitability of NP fragments as leads for development and, in this specific case,t he molecular binding hypothesis probed with 2.…”

Applications of Fluorine in Medicinal Chemistry

“…55 The enzyme exists in two forms, PDGFRα and PDGFRβ, encoded by different genes. Inhibitors of PDGFRβ were sought in an effort to provide tools to illuminate the role of the enzyme in tumor growth, angiogenesis, and fibrosis.…”

Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions

“…In addition, LHMDS couplings have been applied to construct azaheterocycles present in druglike molecules. For instance, Hicken and co-workers (Array BioPharma) 397 and Masumoto and colleagues (Takeda) 398 followed this approach to access heteroarylamines 467 and 469 , respectively, as the source of the imidazopyridine cores in potential cancer therapeutics 468 and 470 ( Scheme 116 b,c). The corresponding 2-chloropyridines reacted with LHMDS in excellent yield with the assistance of dialkylbiarylphosphine-based catalysts.…”