New Pyrazolo[1,5a]pyrimidines as Orally Active Inhibitors of Lck

A novel series of pyrazolo[1,5a]pyrimidines was optimized to target lymphocyte-specific kinase (Lck). An efficient synthetic route was developed and SAR studies towards activity and selectivity are described, leading to Lck inhibitors with enzymatic, cellular and in vivo potency

Discovery and SAR of potent, orally available and brain-penetrable 5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen- and 4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen derivatives as neuropeptide Y Y5 receptor antagonists.

Combination of structural elements from a potent Y5 antagonist (2) with thiazole fragments that exhibit weak Y5 affinities followed by lead optimisation led to the discovery of (5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino and (4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino derivatives. Both classes of compounds are capable of delivering potent and selective orally and centrally bioavailable NPY Y5 receptor antagonists

An oral S1P1 antagonist prodrug with efficacy in vivo: discovery, synthesis and evaluation

A prodrug approach to optimize the oral exposure of an S1P1 antagonist for chronic efficacy studies led to the discovery of (S)-2-{[3'-(4-Chloro-2,5-dimethyl-benzenesulfonylamino)-3,5-dimethyl-biphenyl-4-carbonyl]-methyl-amino}-4-dimethylamino-butyric acid methyl ester (BVM924). Due to the steric hindrance and the partial double bond character of the amide group and the resulting large rotational barrier around the amide bond two conformers of (BVM924) can be detected in solution and their equilibration was investigated by UPLC and 1H NMR. Methyl ester prodrug (BVM924) is hydrolyzed in vivo to the corresponding carboxylic acid (BVS819), a potent and selective S1P1 antagonist. Oral administration of the prodrug (BVM924) induces sustained peripheral lymphocyte depletion in rats. In a rat cardiac transplantation model co-administration of a nonefficacious dose of prodrug (BVM924) with a nonefficacious dose of sotrastaurin (AEB071), a protein kinase C inhibitor, or everolimus (RAD001), an mTOR inhibitor, effectively prolonged the survival time of rat cardiac allografts. This demonstrates that clinically useful immunomodulation mediated by the S1P1 receptor can be achieved with an S1P1 antagonist generated in vivo after oral administration of its prodrug

Novel Syk inhibitors with high potency in presence of blood

We describe two series of Syk inhibitors which potently abrogate Syk kinase function in enzymatic, cellular assays and in primary cells in the presence of blood. Introduction of a 7-aminoindole substituent led to derivatives with good kinase selectivity and little or no hERG channel inhibition (3b, 10c)

A Potent and Selective S1P1 Antagonist with Efficacy in Experimental Autoimmune Encephalomyelitis

SummaryLymphocyte trafficking is critically regulated by the Sphingosine 1-phosphate receptor-1 (S1P1), a G protein-coupled receptor that has been highlighted as a promising therapeutic target in autoimmunity. Fingolimod (FTY720, Gilenya) is a S1P1 receptor agonist that has recently been approved for the treatment of multiple sclerosis (MS). Here, we report the discovery of NIBR-0213, a potent and selective S1P1 antagonist that induces long-lasting reduction of peripheral blood lymphocyte counts after oral dosing. NIBR-0213 showed comparable therapeutic efficacy to fingolimod in experimental autoimmune encephalomyelitis (EAE), a model of human MS. These data provide convincing evidence that S1P1 antagonists are effective in EAE. In addition, the profile of NIBR-0213 makes it an attractive candidate to further study the consequences of S1P1 receptor antagonism and to differentiate the effects from those of S1P1 agonists

An Oral Sphingosine 1‑Phosphate Receptor 1 (S1P₁) Antagonist Prodrug with Efficacy in Vivo: Discovery, Synthesis, and Evaluation

A prodrug approach to optimize the oral exposure of a series of sphingosine 1-phosphate receptor 1 (S1P₁) antagonists for chronic efficacy studies led to the discovery of (<i>S</i>)-2-{[3′-(4-chloro-2,5-dimethylphenylsulfonylamino)-3,5-dimethylbiphenyl-4-carbonyl]­methylamino}-4-dimethylaminobutyric acid methyl ester <b>14</b>. Methyl ester prodrug <b>14</b> is hydrolyzed in vivo to the corresponding carboxylic acid <b>15</b>, a potent and selective S1P₁ antagonist. Oral administration of the prodrug <b>14</b> induces sustained peripheral blood lymphocyte reduction in rats. In a rat cardiac transplantation model coadministration of a nonefficacious dose of prodrug <b>14</b> with a nonefficacious dose of sotrastaurin (<b>19</b>), a protein kinase C inhibitor, or everolimus (<b>20</b>), an mTOR inhibitor, effectively prolonged the survival time of rat cardiac allografts. This demonstrates that clinically useful immunomodulation mediated by the S1P₁ receptor can be achieved with an S1P₁ antagonist generated in vivo after oral administration of its prodrug