We investigated the pharmacology of three novel compounds, Org 27569 (5-chloro-3-ethyl-1H-indole-2-carboxylic acid [2-(4-piperidin-1-yl-phenyl)-ethyl]-amide), Org 27759 (3-ethyl-5-fluoro-1H-indole-2-carboxylic acid [2-94-dimethylamino-phenyl)-ethyl]-amide), and Org 29647 (5-chloro-3-ethyl-1H-indole-2-carboxylic acid (1-benzyl-pyrrolidin-3-yl)-amide, 2-enedioic acid salt), at the cannabinoid CB 1 receptor. In equilibrium binding assays, the Org compounds significantly increased the binding of the CB 1 receptor agonist, indicative of a positively cooperative allosteric effect. The same compounds caused a significant, but incomplete, decrease in the specific binding of the CB 1 receptor inverse agonist studies also validated the allosteric nature of the Org compounds, because they all significantly decreased radioligand dissociation. These data suggest that the Org compounds bind allosterically to the CB 1 receptor and elicit a conformational change that increases agonist affinity for the orthosteric binding site. In contrast to the binding assays, however, the Org compounds behaved as insurmountable antagonists of receptor function; in the reporter gene assay, the guanosine 5Ј-O-(3-[35 S]thio)triphosphate binding assay and the mouse vas deferens assay they elicited a significant reduction in the E max value for CB 1 receptor agonists. The data presented clearly demonstrate, for the first time, that the cannabinoid CB 1 receptor contains an allosteric binding site that can be recognized by synthetic small molecule ligands.Mammalian tissues express at least two types of cannabinoid receptor, CB 1 and CB 2 , both G protein-coupled (for review, see Howlett et al., 2002). CB 1 receptors are found predominantly at central and peripheral nerve terminals where they mediate inhibition of transmitter release. Endogenous ligands for these receptors also exist. These "endocannabinoids" are all eicosanoids, prominent examples including arachidonoylethanolamide (anandamide) and 2-arachidonoyl glycerol, both of which are synthesized on demand, removed from their sites of action by tissue uptake processes and metabolized by intracellular enzymes (Pertwee and Ross,
Indoleamine-2,3-dioxygenase-1
(IDO1) has emerged as a target of
significant interest to the field of cancer immunotherapy, as the
upregulation of IDO1 in certain cancers has been linked to host immune
evasion and poor prognosis for patients. In particular, IDO1 inhibition
is of interest as a combination therapy with immune checkpoint inhibition.
Through an Automated Ligand Identification System (ALIS) screen, a
diamide class of compounds was identified as a promising lead for
the inhibition of IDO1. While hit 1 possessed attractive
cell-based potency, it suffered from a significant right-shift in
a whole blood assay, poor solubility, and poor pharmacokinetic properties.
Through a physicochemical property-based approach, including a focus
on lowering AlogP98 via the strategic introduction of polar
substitution, compound 13 was identified bearing a pyridyl
oxetane core. Compound 13 demonstrated improved whole
blood potency and solubility, and an improved pharmacokinetic profile
resulting in a low predicted human dose.
A novel CB1 receptor agonist lead series was identified using a high-throughput screening approach. The initial screen afforded a single confirmed hit with poor water solubility. Structural variations were explored with the aim of introducing water solubility and improving potency. This led to the discovery of Org 28611, a potent, water soluble CB1 receptor agonist, which was selected for clinical evaluation as a potential intravenous analgesic agent.
A 3042 compound screening library was synthesized using a combination of two solid-phase technologies: REM resin methodology and Lewis acid promoted aminolysis. The exclusivity and structural diversity of the library were enhanced by using a highly divergent synthetic strategy involving 13 different scaffolds (9 of which were custom-made), five different types of resin-bound phenol derivatization chemistry (Mitsunobu, Suzuki, acylation, sulfonylation, and carbamoylation), and three different cleavage strategies (Hofmann elimination, AlCl(3)-promoted aminolysis, base-promoted esterolysis). This is the first example of a solid-phase Suzuki coupling involving a resin-bound aryl triflate being used for library synthesis. Computational analysis suggested that the compounds are likely to have favorable properties for CNS penetration. Analysis of the library by HPLC and MS suggested at least 90% of the sampled members were present in an average purity of approximately 70%. Encouragingly, hits have been identified from high-throughput screening of this library, such as compound 6, which has an affinity of 1.02 microM for the GlyT(2) transporter.
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