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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 PDGFR? 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.

SUBMITTER: Hicken EJ

PROVIDER: S-EPMC4027622 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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

Hicken Erik J EJ Marmsater Fred P FP Munson Mark C MC Schlachter Stephen T ST Robinson John E JE Allen Shelley S Burgess Laurence E LE DeLisle Robert Kirk RK Rizzi James P JP Topalov George T GT Zhao Qian Q Hicks Julie M JM Kallan Nicholas C NC Tarlton Eugene E Allen Andrew A Callejo Michele M Cox April A Rana Sumeet S Klopfenstein Nathalie N Woessner Richard R Lyssikatos Joseph P JP

ACS medicinal chemistry letters 20131112 1

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 eff ...[more]

PMID: 24900776

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Project description:Based on a previously identified antileishmanial 6,8-dibromo-3-nitroimidazo[1,2-a]pyridine derivative, a Suzuki-Miyaura coupling reaction at position 8 of the scaffold was studied and optimized from a 8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine substrate. Twenty-one original derivatives were prepared, screened in vitro for activity against L. infantum axenic amastigotes and T. brucei brucei trypomastigotes and evaluated for their cytotoxicity on the HepG2 human cell line. Thus, 7 antileishmanial hit compounds were identified, displaying IC50 values in the 1.1-3 μM range. Compounds 13 and 23, the 2 most selective molecules (SI = >18 or >17) were additionally tested on both the promastigote and intramacrophage amastigote stages of L. donovani. The two molecules presented a good activity (IC50 = 1.2-1.3 μM) on the promastigote stage but only molecule 23, bearing a 4-pyridinyl substituent at position 8, was active on the intracellular amastigote stage, with a good IC50 value (2.3 μM), slightly lower than the one of miltefosine (IC50 = 4.3 μM). The antiparasitic screening also revealed 8 antitrypanosomal hit compounds, including 14 and 20, 2 very active (IC50 = 0.04-0.16 μM) and selective (SI = >313 to 550) molecules toward T. brucei brucei, in comparison with drug-candidate fexinidazole (IC50 = 0.6 & SI > 333) or reference drugs suramin and eflornithine (respective IC50 = 0.03 and 13.3 μM). Introducing an aryl moiety at position 8 of the scaffold quite significantly increased the antitrypanosomal activity of the pharmacophore. Antikinetoplastid molecules 13, 14, 20 and 23 were assessed for bioactivation by parasitic nitroreductases (either in L. donovani or in T. brucei brucei), using genetically modified parasite strains that over-express NTRs: all these molecules are substrates of type 1 nitroreductases (NTR1), such as those that are responsible for the bioactivation of fexinidazole. Reduction potentials measured for these 4 hit compounds were higher than that of fexinidazole (-0.83 V), ranging from -0.70 to -0.64 V.

Dataset Information

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

Publications

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

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