6 research outputs found
Circumventing Seizure Activity in a Series of G Protein Coupled Receptor 119 (GPR119) Agonists
Agonism of GPR119 is viewed as a
potential therapeutic approach
for the treatment of type II diabetes and other elements of metabolic
syndrome. During progression of a previously disclosed candidate <b>1</b> through mice toxicity studies, we observed tonicâclonic
convulsions in several mice at high doses. An in vitro hippocampal
brain slice assay was used to assess the seizure liability of subsequent
compounds, leading to the identification of an aryl sulfone as a replacement
for the 3-cyano pyridyl group. Subsequent optimization to improve
the overall profile, specifically with regard to hERG activity, led
to alkyl sulfone <b>16</b>. This compound did not cause tonicâclonic
convulsions in mice, had a good pharmacokinetic profile, and displayed
in vivo efficacy in murine models. Importantly, it was shown to be
effective in wild-type (WT) but not GPR119 knockout (KO) animals,
consistent with the pharmacology observed being due to agonism of
GPR119
<i>N</i>âAryl-2-aminobenzimidazoles: Novel, Efficacious, Antimalarial Lead Compounds
From
the phenotypic screening of the AstraZeneca corporate compound
collection, <i>N</i>-aryl-2-aminobenzimidazoles have emerged
as novel hits against the asexual blood stage of <i>Plasmodium
falciparum</i> (<i>Pf</i>). Medicinal chemistry optimization
of the potency against <i>Pf</i> and ADME properties resulted
in the identification of <b>12</b> as a lead molecule. Compound <b>12</b> was efficacious in the <i>P. berghei</i> (<i>Pb</i>) model of malaria. This compound displayed an excellent
pharmacokinetic profile with a long half-life (19 h) in rat blood.
This profile led to an extended survival of animals for over 30 days
following a dose of 50 mg/kg in the <i>Pb</i> malaria model.
Compound <b>12</b> retains its potency against a panel of <i>Pf</i> isolates with known mechanisms of resistance. The fast
killing observed in the <i>in vitro</i> parasite reduction
ratio (PRR) assay coupled with the extended survival highlights the
promise of this novel chemical class for the treatment of malaria
Aminoazabenzimidazoles, a Novel Class of Orally Active Antimalarial Agents
Whole-cell high-throughput
screening of the AstraZeneca compound
library against the asexual blood stage of Plasmodium
falciparum (<i>Pf</i>) led to the identification
of amino imidazoles, a robust starting point for initiating a hit-to-lead
medicinal chemistry effort. Structureâactivity relationship
studies followed by pharmacokinetics optimization resulted in the
identification of <b>23</b> as an attractive lead with good
oral bioavailability. Compound <b>23</b> was found to be efficacious
(ED<sub>90</sub> of 28.6 mg¡kg<sup>â1</sup>) in the humanized P. falciparum mouse model of malaria (<i>Pf</i>/SCID model). Representative compounds displayed a moderate to fast
killing profile that is comparable to that of chloroquine. This series
demonstrates no cross-resistance against a panel of <i>Pf</i> strains with mutations to known antimalarial drugs, thereby suggesting
a novel mechanism of action for this chemical class
4âAminoquinolone Piperidine Amides: Noncovalent Inhibitors of DprE1 with Long Residence Time and Potent Antimycobacterial Activity
4-Aminoquinolone piperidine amides
(AQs) were identified as a novel
scaffold starting from a whole cell screen, with potent cidality on Mycobacterium tuberculosis (Mtb). Evaluation of the
minimum inhibitory concentrations, followed by whole genome sequencing
of mutants raised against AQs, identified decaprenylphosphoryl-β-d-ribose 2â˛-epimerase (DprE1) as the primary target responsible
for the antitubercular activity. Mass spectrometry and enzyme kinetic
studies indicated that AQs are noncovalent, reversible inhibitors
of DprE1 with slow on rates and long residence times of âź100
min on the enzyme. In general, AQs have excellent leadlike properties
and good in vitro secondary pharmacology profile. Although the scaffold
started off as a single active compound with moderate potency from
the whole cell screen, structureâactivity relationship optimization
of the scaffold led to compounds with potent DprE1 inhibition (IC<sub>50</sub> < 10 nM) along with potent cellular activity (MIC = 60
nM) against Mtb
Discovery of Imidazo[1,2â<i>a</i>]pyridine Ethers and Squaramides as Selective and Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthesis
The approval of bedaquiline
to treat tuberculosis has validated
adenosine triphosphate (ATP) synthase as an attractive target to kill Mycobacterium tuberculosis (Mtb). Herein, we report
the discovery of two diverse lead series imidazoÂ[1,2-<i>a</i>]Âpyridine ethers (IPE) and squaramides (SQA) as inhibitors of mycobacterial
ATP synthesis. Through medicinal chemistry exploration, we established
a robust structureâactivity relationship of these two scaffolds,
resulting in nanomolar potencies in an ATP synthesis inhibition assay.
A biochemical deconvolution cascade suggested cytochrome c oxidase
as the potential target of IPE class of molecules, whereas characterization
of spontaneous resistant mutants of SQAs unambiguously identified
ATP synthase as its molecular target. Absence of cross resistance
against bedaquiline resistant mutants suggested a different binding
site for SQAs on ATP synthase. Furthermore, SQAs were found to be
noncytotoxic and demonstrated efficacy in a mouse model of tuberculosis
infection
Discovery of Imidazo[1,2â<i>a</i>]pyridine Ethers and Squaramides as Selective and Potent Inhibitors of Mycobacterial Adenosine Triphosphate (ATP) Synthesis
The approval of bedaquiline
to treat tuberculosis has validated
adenosine triphosphate (ATP) synthase as an attractive target to kill Mycobacterium tuberculosis (Mtb). Herein, we report
the discovery of two diverse lead series imidazoÂ[1,2-<i>a</i>]Âpyridine ethers (IPE) and squaramides (SQA) as inhibitors of mycobacterial
ATP synthesis. Through medicinal chemistry exploration, we established
a robust structureâactivity relationship of these two scaffolds,
resulting in nanomolar potencies in an ATP synthesis inhibition assay.
A biochemical deconvolution cascade suggested cytochrome c oxidase
as the potential target of IPE class of molecules, whereas characterization
of spontaneous resistant mutants of SQAs unambiguously identified
ATP synthase as its molecular target. Absence of cross resistance
against bedaquiline resistant mutants suggested a different binding
site for SQAs on ATP synthase. Furthermore, SQAs were found to be
noncytotoxic and demonstrated efficacy in a mouse model of tuberculosis
infection