In the present study three different procedures have been compared for the determination of the lipophilicity of the unionized species (log P) of neutral, acidic, basic, amphoteric, and zwitterionic drugs. Shake-flask, potentiometric and chromatographic approaches have been assayed in a set of 66 representative compounds in different phases of advanced development. An excellent equivalence has been found between log P values obtained by shake-flask and potentiometry, while the chromatographic approach is less accurate but very convenient for screening purposes when a high-throughput is required. In the case of zwitterionic and amphoteric compounds, either for shake-flask and chromatographic methods, the pH has to be accurately selected in order to ensure the compound to be in its neutral form.
The synthesis and pharmacological activity of a new series of hexahydro-2H-pyrano[3,2-c]quinoline derivatives as potent σ1 receptor (σ1R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other σ1R ligands, showed high selectivity over the σ2 receptor (σ2R). The activity was shown to reside in only one of the four possible diastereoisomers, which exhibited a perfect match with known σ1R pharmacophores. A hit to lead program based on a high-throughput screening hit (8a) led to the identification of compound 32c, with substantially improved activity and physicochemical properties. Compound 32c also exhibited a good ADMET (absorption, distribution, metabolism, excretion, toxicity) profile and was identified as a σ1R antagonist on the basis of its analgesic activity in the mouse capsaicin and formalin models of neurogenic pain.
Co-crystal of tramadol–celecoxib
(CTC) is a novel active
pharmaceutical ingredient API–API co-crystal formed by an intrinsic
1:1 molecular ratio of rac-tramadol·HCl (TRM)
and celecoxib (CXB) in late-stage development for the treatment of
pain. In line with previous intrinsic dissolution rate studies, we
report here that the kinetic dissolution profile of CTC in hydroxypropyl
methyl cellulose and buffered solutions led to a supersaturation state
of CXB and a release significantly faster from CTC than from the free
combination, which in turn was quite similar to the release from CXB
alone. Inversely, TRM was released much more slowly from CTC than
from the free combination and TRM alone. Experimental and predicted
solubility–pH curves showed that the thermodynamic solubility
of CTC lies in between those of TRM and CXB within the physiologically
meaningful pH range. The lattice and solvation contributions to CTC
aqueous solubility was studied, showing that the solvation factor
is the most important, but it appears to be proportionally lower and
more similar to the more soluble component, TRM. These results, together
with those obtained in the hygroscopicity studies, show that CTC co-crystal
structure provides a clear differential profile versus the free combination
or the two APIs alone.
The synthesis of a new series of 4-acylaminopyrazolo[3,4-]pyrimidines active on the sigma-1 receptor (σR) is reported. Compounds were efficiently prepared using a two to three step process starting from commercially available 1-pyrazolo[3,4-]pyrimidin-4-amine. A SAR study shows that the σR requires the presence of relatively highly lipophilic substituents at opposite sides of the central scaffold, while selectivity the σR can be improved by shortening the distance of the basic nitrogen to it. Compound was among the most active and selective derivatives and exhibited potent antinociceptive properties in several pain models in mice, indicating its antagonistic behaviour.
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