9 research outputs found
Novel S1P<sub>1</sub> Receptor Agonists - Part 2: From Bicyclo[3.1.0]hexane-Fused Thiophenes to Isobutyl Substituted Thiophenes
Previously, we reported on the discovery
of a novel series of bicyclo[3.1.0]Âhexane
fused thiophene derivatives that serve as potent and selective S1P<sub>1</sub> receptor agonists. Here, we discuss our efforts to simplify
the bicyclohexane fused thiophene head. In a first step the bicyclohexane
moiety could be replaced by a simpler, less rigid cyclohexane ring
without compromising the S1P receptor affinity profile of these novel
compounds. In a second step, the thiophene head was simplified even
further by replacing the cyclohexane ring with an isobutyl group attached
either to position 4 or position 5 of the thiophene. These structurally
much simpler headgroups again furnished potent and selective S1P<sub>1</sub> agonists (e.g., <b>87</b>), which efficiently and dose
dependently reduced the number of circulating lymphocytes upon oral
administration to male Wistar rats. For several compounds discussed
in this report lymphatic transport is an important route of absorption
that may offer opportunities for a tissue targeted approach with minimal
plasma exposure
Novel S1P<sub>1</sub> Receptor Agonists – Part 1: From Pyrazoles to Thiophenes
From
a high-throughput screening campaign aiming at the identification
of novel S1P<sub>1</sub> receptor agonists, the pyrazole derivative <b>2</b> emerged as a hit structure. Medicinal chemistry efforts
focused not only on improving the potency of the compound but in particular
also on resolving its inherent instability issue. This led to the
discovery of novel bicyclo[3.1.0]Âhexane fused thiophene derivatives.
Compounds with high affinity and selectivity for S1P<sub>1</sub> efficiently
reducing the blood lymphocyte count in the rat were identified. For
instance, compound <b>85</b> showed EC<sub>50</sub> values of
7 and 2880 nM on S1P<sub>1</sub> and S1P<sub>3</sub>, respectively,
had favorable pharmacokinetic properties in rat and dog, distributed
well into brain tissue, and efficiently and dose dependently reduced
the blood lymphocyte count in the rat. After oral administration to
spontaneously hypertensive rats, the S1P<sub>1</sub> selective compound <b>85</b> showed no effect on mean arterial blood pressure and affected
the heart rate during the wake phase of the animals only
Novel S1P<sub>1</sub> Receptor Agonists − Part 3: From Thiophenes to Pyridines
In
preceding communications we summarized our medicinal chemistry
efforts leading to the identification of potent, selective, and orally
active S1P<sub>1</sub> agonists such as the thiophene derivative <b>1</b>. As a continuation of these efforts, we replaced the thiophene
in <b>1</b> by a 2-, 3-, or 4-pyridine and obtained less lipophilic,
potent, and selective S1P<sub>1</sub> agonists (e.g., <b>2</b>) efficiently reducing blood lymphocyte count in the rat. Structural
features influencing the compounds’ receptor affinity profile
and pharmacokinetics are discussed. In addition, the ability to penetrate
brain tissue has been studied for several compounds. As a typical
example for these pyridine based S1P<sub>1</sub> agonists, compound <b>53</b> showed EC<sub>50</sub> values of 0.6 and 352 nM for the
S1P<sub>1</sub> and S1P<sub>3</sub> receptor, respectively, displayed
favorable PK properties, and penetrated well into brain tissue. In
the rat, compound <b>53</b> maximally reduced the blood lymphocyte
count for at least 24 h after oral dosing of 3 mg/kg