Novel S1P₁ Receptor Agonists - Part 2: From Bicyclo[3.1.0]hexane-Fused Thiophenes to Isobutyl Substituted Thiophenes

Abstract

Previously, we reported on the discovery of a novel series of bicyclo[3.1.0]hexane fused thiophene derivatives that serve as potent and selective S1P1 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 S1P1 agonists (e.g., 87), 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.

Modulators of Sphingosine-1-phosphate Pathway Biology: Recent Advances of Sphingosine-1-phosphate Receptor 1 (S1P1) Agonists and Future Perspectives

“…For example, replacement of the central phenyl ring with a substituted pyridine (39) provided a compound capable of inducing lymphopenia in rats after oral dosing. 47 In the structurally unique diphenylethyne compound 40, a pendant imidazole serves as the headgroup to provide a potent S1P 1 agonist. 48 With a basic amino-alcohol polar group, phenyl ether 41 was designed to be a potent direct-acting S1P 1 agonist and it was shown to elicit lymphopenia in rats after oral dosing.…”

Pd-Catalyzed ipso,meta-Dimethylation of ortho-Substituted Iodoarenes via a Base-Controlled C–H Activation Cascade with Dimethyl Carbonate as the Methyl Source

“…Many of the 2,6-dimethylated anisole products, such as 3f , 3g , 3h , 3i , 3k , 3l , 3o , and 3p ,, and their demethylated analogues, the 2,6-dimethylphenols, − are essential intermediates in the syntheses of biologically and pharmacologically active compounds (Figure c). Demethylation of the 2,6-dimethylanisole products was exemplified by the reactions of 3f and 3f - D (Figure b).…”

The Discovery of Macitentan – A Standard Medicinal Chemistry Program?

“…While the thiophene ketones lose activity (LC>-60%), the oxadiazole derivatives still show sustained LC reduction (LC <-70%). Some of the oxadiazoles even gained activity at 24 h. [77,78] A similar analysis revealed clear differences between potent S1P 1 agonists incorporating either a 2-or a 4-pyridine substituted properties were also suggested to be responsible for macitentan's increased distribution into lung and right ventricle tissue in rats with bleomycin and monocrotalin induced pulmonary hypertension. [54,71] To investigate whether these differences in receptor binding kinetics and tissue distribution were pharmacologically meaningful, macitentan was administered on top of a maximally efficacious dose of bosentan to hypertensive Dahl salt-sensitive rats.…”