5 research outputs found
Antikinetoplastid SAR study in 3-nitroimidazopyridine series: identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties
To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = -0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program
Validation of the in vitro comet assay for DNA cross‑links and altered bases detection
Mechanistic toxicology is gaining weight for human health risk assessment. Different mechanistic assays are available, such
as the comet assay, which detects DNA damage at the level of individual cells. However, the conventional alkaline version
only detects strand breaks and alkali-labile sites. We have validated two modifications of the in vitro assay to generate mechanistic
information: (1) use of DNA-repair enzymes (i.e., formamidopyrimidine DNA glycosylase, endonuclease III, human
8-oxoguanine DNA glycosylase I and human alkyladenine DNA glycosylase) for detection of oxidized and alkylated bases
as well as (2) a modification for detecting cross-links. Seven genotoxicants with different mechanisms of action (potassium
bromate, methyl methanesulfonate, ethyl methanesulfonate, hydrogen peroxide, cisplatin, mitomycin C, and benzo[a]pyrene
diol epoxide), as well as a non-genotoxic compound (dimethyl sulfoxide) and a cytotoxic compound (Triton X-100) were
tested on TK-6 cells. We were able to detect with high sensitivity and clearly differentiate oxidizing, alkylating and crosslinking
agents. These modifications of the comet assay significantly increase its sensitivity and its specificity towards DNA
lesions, providing mechanistic information regarding the type of damage
Taking advantage of the selectivity of histone deacetylases and phosphodiesterase inhibitors to design better therapeutic strategies to treat alzheimer’s disease
The discouraging results with therapies for Alzheimer’s disease (AD) in clinical trials,
highlights the urgent need to adopt new approaches. Like other complex diseases,
it is becoming clear that AD therapies should focus on the simultaneous modulation
of several targets implicated in the disease. Recently, using reference compounds
and the first-in class CM-414, we demonstrated that the simultaneous inhibition
of histone deacetylases [class I histone deacetylases (HDACs) and HDAC6] and
phosphodiesterase 5 (PDE5) has a synergistic therapeutic effect in AD models. To identify
the best inhibitory balance of HDAC isoforms and PDEs that provides a safe and efficient
therapy to combat AD, we tested the compound CM-695 in the Tg2576 mouse model
of this disease. CM-695 selectively inhibits HDAC6 over class I HDAC isoforms, which
largely overcomes the toxicity associated with HDAC class 1 inhibition. Furthermore,
CM-695 inhibits PDE9, which is expressed strongly in the brain and has been proposed
as a therapeutic target for AD. Chronic treatment of aged Tg2576 mice with CM-695
ameliorates memory impairment and diminishes brain Aβ, although its therapeutic effect
was no longer apparent 4 weeks after the treatment was interrupted. An increase in
the presence of 78-KDa glucose regulated protein (GRP78) and heat shock protein 70
(Hsp70) chaperones may underlie the therapeutic effect of CM-695. In summary, chronic
treatment with CM-695 appears to reverse the AD phenotype in a safe and effective
manner. Taking into account that AD is a multifactorial disorder, the multimodal action
of these compounds and the different events they affect may open new avenues to
combat AD
Taking advantage of the selectivity of histone deacetylases and phosphodiesterase inhibitors to design better therapeutic strategies to treat alzheimer’s disease
The discouraging results with therapies for Alzheimer’s disease (AD) in clinical trials,
highlights the urgent need to adopt new approaches. Like other complex diseases,
it is becoming clear that AD therapies should focus on the simultaneous modulation
of several targets implicated in the disease. Recently, using reference compounds
and the first-in class CM-414, we demonstrated that the simultaneous inhibition
of histone deacetylases [class I histone deacetylases (HDACs) and HDAC6] and
phosphodiesterase 5 (PDE5) has a synergistic therapeutic effect in AD models. To identify
the best inhibitory balance of HDAC isoforms and PDEs that provides a safe and efficient
therapy to combat AD, we tested the compound CM-695 in the Tg2576 mouse model
of this disease. CM-695 selectively inhibits HDAC6 over class I HDAC isoforms, which
largely overcomes the toxicity associated with HDAC class 1 inhibition. Furthermore,
CM-695 inhibits PDE9, which is expressed strongly in the brain and has been proposed
as a therapeutic target for AD. Chronic treatment of aged Tg2576 mice with CM-695
ameliorates memory impairment and diminishes brain Aβ, although its therapeutic effect
was no longer apparent 4 weeks after the treatment was interrupted. An increase in
the presence of 78-KDa glucose regulated protein (GRP78) and heat shock protein 70
(Hsp70) chaperones may underlie the therapeutic effect of CM-695. In summary, chronic
treatment with CM-695 appears to reverse the AD phenotype in a safe and effective
manner. Taking into account that AD is a multifactorial disorder, the multimodal action
of these compounds and the different events they affect may open new avenues to
combat AD
Antikinetoplastid SAR study in 3-nitroimidazopyridine series: identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties
To study the antikinetoplastid 3-nitroimidazo[1,2-a]pyridine pharmacophore, a structure-activity relationship study was conducted through the synthesis of 26 original derivatives and their in vitro evaluation on both Leishmania spp and Trypanosoma brucei brucei. This SAR study showed that the antitrypanosomal pharmacophore was less restrictive than the antileishmanial one and highlighted positions 2, 6 and 8 of the imidazopyridine ring as key modulation points. None of the synthesized compounds allowed improvement in antileishmanial activity, compared to previous hit molecules in the series. Nevertheless, compound 8, the best antitrypanosomal molecule in this series (EC50 = 17 nM, SI = 2650 & E° = -0.6 V), was not only more active than all reference drugs and previous hit molecules in the series but also displayed improved aqueous solubility and better in vitro pharmacokinetic characteristics: good microsomal stability (T1/2 > 40 min), moderate albumin binding (77%) and moderate permeability across the blood brain barrier according to a PAMPA assay. Moreover, both micronucleus and comet assays showed that nitroaromatic molecule 8 was not genotoxic in vitro. It was evidenced that bioactivation of molecule 8 was operated by T. b. brucei type 1 nitroreductase, in the same manner as fexinidazole. Finally, a mouse pharmacokinetic study showed that 8 displayed good systemic exposure after both single and repeated oral administrations at 100 mg/kg (NOAEL) and satisfying plasmatic half-life (T1/2 = 7.7 h). Thus, molecule 8 appears as a good candidate for initiating a hit to lead drug discovery program