ABSTRACT
A concise, enantioselective synthesis of the potent dual orexin inhibitor suvorexant (1) is reported. Key features of the synthesis include a mild copper-catalyzed amination, a highly chemoselective conjugate addition, and a tandem enantioselective transamination/seven-membered ring annulation. The synthesis requires inexpensive starting materials and only four linear steps for completion.
Subject(s)
Azepines/chemical synthesis , Triazoles/chemical synthesis , Azepines/chemistry , Azepines/pharmacology , Molecular Structure , Orexin Receptors , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, Neuropeptide/antagonists & inhibitors , Stereoisomerism , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C-N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1-3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.
Subject(s)
Anemia/drug therapy , Aza Compounds/chemical synthesis , Hydantoins/chemical synthesis , Hypoxia-Inducible Factor 1/metabolism , Procollagen-Proline Dioxygenase/antagonists & inhibitors , Spiro Compounds/chemical synthesis , Animals , Aza Compounds/pharmacokinetics , Aza Compounds/pharmacology , Dogs , ERG1 Potassium Channel , Erythropoietin/biosynthesis , Ether-A-Go-Go Potassium Channels/metabolism , High-Throughput Screening Assays , Humans , Hydantoins/pharmacokinetics , Hydantoins/pharmacology , Hypoxia-Inducible Factor-Proline Dioxygenases , Indoles/chemical synthesis , Indoles/pharmacokinetics , Indoles/pharmacology , Liver/drug effects , Liver/enzymology , Macaca mulatta , Mass Spectrometry , Mice , Mice, Inbred C57BL , Protein Binding , Rats , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacology , Structure-Activity Relationship , Up-RegulationABSTRACT
Pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis. Here, we report an efficient biocatalytic process to replace a recently implemented rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of the antidiabetic compound sitagliptin. Starting from an enzyme that had the catalytic machinery to perform the desired chemistry but lacked any activity toward the prositagliptin ketone, we applied a substrate walking, modeling, and mutation approach to create a transaminase with marginal activity for the synthesis of the chiral amine; this variant was then further engineered via directed evolution for practical application in a manufacturing setting. The resultant biocatalysts showed broad applicability toward the synthesis of chiral amines that previously were accessible only via resolution. This work underscores the maturation of biocatalysis to enable efficient, economical, and environmentally benign processes for the manufacture of pharmaceuticals.
Subject(s)
Amines/chemical synthesis , Directed Molecular Evolution , Hypoglycemic Agents/chemical synthesis , Ketones/chemistry , Protein Engineering , Pyrazines/chemical synthesis , Transaminases/chemistry , Triazoles/chemical synthesis , Biocatalysis , Catalytic Domain , Hypoglycemic Agents/metabolism , Ketones/metabolism , Models, Molecular , Molecular Structure , Mutagenesis , Protein Conformation , Pyrazines/metabolism , Sitagliptin Phosphate , Solubility , Stereoisomerism , Substrate Specificity , Transaminases/genetics , Transaminases/metabolism , Triazoles/metabolismABSTRACT
[reaction: see text] Trifluoropropanoic acid reacts with 1 equiv of POCl3 in DMF to generate the trifluoromethyl enamine (7). At this stage, two reaction manifolds are available. The expected reaction with additional POCl3 generates the 2-trifluoromethyl vinamidinium salt (3c). However, thermally driven loss of fluoride generates an iminium ion, which sets the stage for a [2 + 2] cycloaddition to ultimately generate the dimethylaminomethylene vinamidinium salt (1).