Discovery of AMG 369, a Thiazolo[5,4-b]pyridine Agonist of S1P₁ and S1P₅

Abstract

The optimization of a series of thiazolopyridine S1P1 agonists with limited activity at the S1P3 receptor is reported. These efforts resulted in the discovery of 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo-[5,4-b]pyridin-2-yl)benzyl)azetidine-3-carboxylic acid (5d, AMG 369), a potent dual S1P1/S1P5 agonist with limited activity at S1P3 and no activity at S1P2/S1P4. Dosed orally at 0.1 mg/kg, 5d is shown to reduce blood lymphocyte counts 24 h postdose and delay the onset and reduce the severity of experimental autoimmune encephalomyelitis in rat.

An update on sphingosine-1-phosphate receptor 1 modulators

“…95 AMG 369 acts as a potent S1P 1 and S1P 5 agonist, showing low S1P 3 activity and being inactive towards S1P 2 and S1P 4 . 95 The absence of cardiovascular effects even at concentrations as high as 10 mg/kg of AMG 369 in rats further indicate the correlation of bradycardia with S1P 3 agonism in the rodent model.…”

“…95 AMG 369 acts as a potent S1P 1 and S1P 5 agonist, showing low S1P 3 activity and being inactive towards S1P 2 and S1P 4 . 95 The absence of cardiovascular effects even at concentrations as high as 10 mg/kg of AMG 369 in rats further indicate the correlation of bradycardia with S1P 3 agonism in the rodent model. 82,95 Oral bioavailability was found to range between 34–64% in rat, dog, and non–human primate experiments, and a depletion of PDL counts 24 hrs after oral administration of 0.1 mg/kg led to a significant delay of EAE onset in the rat model.…”

“…82,95 Oral bioavailability was found to range between 34–64% in rat, dog, and non–human primate experiments, and a depletion of PDL counts 24 hrs after oral administration of 0.1 mg/kg led to a significant delay of EAE onset in the rat model. 95 …”

Modulators of the Sphingosine 1-phosphate receptor 1

“…Pursuing novel S1P 3 -R–sparing S1P 1 -R agonists, Amgen concomitantly modified the azetidine carboxylate head-group of AMG369 while keeping its lipophilic tail (Table 7). 40-41 Of note, 3-amino succinamic acids 23a, 23b and α-methyl-α-aminobutyrate (–)- 23c proved exceptionally potent S1P 1 -R agonists with EC 50 ’s in sub-nanomolar range and highly selective against the S1P 3 -R. The selectivity at the S1P 5 -R was not provided even though AMG369 was previously reported to have a nanomolar S1P 5 -R agonist activity. 41 Amongst the explored molecules, 23c showed the best efficacy in reducing PBL counts following oral dosing in rats at 1 mg/kg, and moderate lymphocyte depletion could be observed even at 0.3 mg/kg.…”

4-Methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide: A Potent and Selective Agonist of S1P1

“…The 24 h time point was selected for our studies, as it was found to mitigate the effects of dosing on lymphocyte counts. 17 Notably, carbamoylnicotinamide 8 reaches >5-fold higher concentration in plasma than the other compounds tested in Table 1 (64 ng/mL) and is also the only one that effects statistically significant (P < 0.05 vs vehicle by the ANOVA/Dunnett's multiple comparison test) reduction in circulating lymphocytes (POC = À67%). Given their comparable in vitro profiles, it is unclear why compounds 14À16 and 18 do not achieve higher plasma levels and realize statistically significant reduction of peripheral lymphocyte counts (PLCs).…”