Novel S1P₁ Receptor Agonists − Part 3: From Thiophenes to Pyridines

Abstract

In preceding communications we summarized our medicinal chemistry efforts leading to the identification of potent, selective, and orally active S1P1 agonists such as the thiophene derivative 1. As a continuation of these efforts, we replaced the thiophene in 1 by a 2-, 3-, or 4-pyridine and obtained less lipophilic, potent, and selective S1P1 agonists (e.g., 2) 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 S1P1 agonists, compound 53 showed EC50 values of 0.6 and 352 nM for the S1P1 and S1P3 receptor, respectively, displayed favorable PK properties, and penetrated well into brain tissue. In the rat, compound 53 maximally reduced the blood lymphocyte count for at least 24 h after oral dosing of 3 mg/kg.

The Discovery of Macitentan – A Standard Medicinal Chemistry Program?

“…At 24 the 2-pyridines clearly lose activity while most of the 4-pyridines retain full efficacy. [79][80][81]…”

Discovery of Tetrahydropyrazolopyridine as Sphingosine 1-Phosphate Receptor 3 (S1P3)-Sparing S1P1 Agonists Active at Low Oral Doses

“…As our internal screening effort did not identify hits of significant interest (lack of potency, druglikeness, and/or tractability), we decided to identify new S1P 1 agonists from the triaryl motif shown above. Previous SAR from our group or others had shown that modification of the distal trisubstituted aromatic led to significant drop in potency in most, but not all, − cases, while the oxadiazole central ring could be substituted without significant change in potency or selectivity, with a thiadiazole for example . With these data in hand, we tried identifying a novel motif to replace the bicyclic amine incorporated in all our agonists, with the aim of keeping our agonists in what has been recently identified as the chemical space least likely to lead to toxicity (cLogP < 3, PSA > 75 Å 2 ). , This was most likely to be achieved by introducing subsituents containing heteroatoms, including basic nitrogen and acidic functionality.…”

Efficient Syntheses of Ethyl 2-Methylthio- and Ethyl 2-Benzylthio-6-methyl(aryl)pyrimidine-4-carboxylates and Their Carboxylic Acid Derivatives

“…6 In a search of the literature, we found six methods described for the preparation of alkyl 2-methylthiopyrimidine-4-carboxylates and/or their corresponding carboxylic acid derivatives, which were, in some ways, similar to our reported method. [7][8][9][10][11][12][13][14] Four of these patented methods reported only the synthesis of 6-unsubstituted alkyl 2-methylthiopyrimidine-4-carboxylates and/or their corresponding carboxylic acid derivatives. [7][8][9][10] A fifth method, widely used in two patents by Haddida 11 and Bolli, 12 relied on the preparation of an extended series of 6-substituted alkyl 2methylthiopyrimidine-4-carboxylates, and/or their corresponding carboxylic acid derivatives, via the cyclocondensation of alkyl 2,4-dioxopentanoates and/or their carboxylic acid derivatives with 2-methylisothiourea sulfate.…”

“…[7][8][9][10][11][12][13][14] Four of these patented methods reported only the synthesis of 6-unsubstituted alkyl 2-methylthiopyrimidine-4-carboxylates and/or their corresponding carboxylic acid derivatives. [7][8][9][10] A fifth method, widely used in two patents by Haddida 11 and Bolli, 12 relied on the preparation of an extended series of 6-substituted alkyl 2methylthiopyrimidine-4-carboxylates, and/or their corresponding carboxylic acid derivatives, via the cyclocondensation of alkyl 2,4-dioxopentanoates and/or their carboxylic acid derivatives with 2-methylisothiourea sulfate. 11,12 This method is similar to our method, but instead uses alkyl 2,4dioxopentanoates instead of 4-alkoxy-2-oxo-4-substituted-but-3-enoates as dielectrophiles, and also employs different reaction conditions to achieve the target compounds.…”

“…[7][8][9][10] A fifth method, widely used in two patents by Haddida 11 and Bolli, 12 relied on the preparation of an extended series of 6-substituted alkyl 2methylthiopyrimidine-4-carboxylates, and/or their corresponding carboxylic acid derivatives, via the cyclocondensation of alkyl 2,4-dioxopentanoates and/or their carboxylic acid derivatives with 2-methylisothiourea sulfate. 11,12 This method is similar to our method, but instead uses alkyl 2,4dioxopentanoates instead of 4-alkoxy-2-oxo-4-substituted-but-3-enoates as dielectrophiles, and also employs different reaction conditions to achieve the target compounds. The sixth method, reported by Piotrowski et al, 13 is similar to that described by Xu et al, 7 in which a single enamino pyruvate was generated and reacted with 2-methylisothiourea sulfate to afford ethyl 2-(methylthio)-5,6,7,8-tetrahydropyrido [4,3-d]pyrimidine-4-carboxylate; this product has been used in further derivatization reactions.…”