The synthesis of sterically hindered amides.

Amide bond formation is one of the most important reactions due to the ubiquity of the amide functional group in pharmaceuticals and biologically active compounds. However, even the best existing methods reach their limits when it comes to the synthesis of sterically hindered amides. In this article we summarize our research in the formation of sterically hindered amides. We show that the direct coupling of Grignard reagents to isocyanates provides a facile and robust solution to this long-standing challenge and hope that this methodology will find widespread application in the synthesis of pharmaceuticals and materials.

Sandmeyer Chlorosulfonylation of (Hetero)Aromatic Amines Using DABSO as an SO2 Surrogate.

Sulfonyl chlorides not only play a crucial role in protecting group chemistry but also are important starting materials in the synthesis of sulfonamides, which are in-demand motifs in drug discovery chemistry. Despite their importance, the number of different synthetic approaches to sulfonyl chlorides is limited, and most of them rely on traditional oxidative chlorination chemistry from thiol precursors. In this report, we disclose a novel Sandmeyer-type sulfonyl chloride synthesis from feedstock anilines and DABSO, used as a stable SO2 surrogate, in the presence of HCl and a Cu catalyst. The method works on a wide range of anilines and allows for the isolation of the sulfonyl chloride after aqueous workup or its direct conversion into the sulfonamide by simple addition of an amine after the completion of the Sandmeyer reaction. The scalability of this method was demonstrated on a 20 g scale, and the corresponding heterocyclic sulfonyl chloride was isolated in 80% yield and excellent purity.

Discovery of the Clinical Candidate IDOR-1117-2520: A Potent and Selective Antagonist of CCR6 for Autoimmune Diseases.

Migration of immune cells to sites of inflammation is a critical step in the body's response to infections but also during autoimmune flares. Chemokine receptors, members of the GPCR receptors, are instrumental in directing specific cell types to their target organs. Herein, we describe a highly potent small molecule antagonist of the chemokine receptor CCR6, which came out of fine-tuned structural elaborations from a proprietary HTS hit. Three main issues in the parent chemical series-cytotoxicity, phototoxicity, and hERG, were successfully solved. Biological characterization demonstrated that compound 45 (IDOR-1117-2520) is a selective and insurmountable antagonist of CCR6. In vivo proof-of-mechanism studies in a mouse lung inflammation model using a representative compound from the chemical class of 45 confirmed that the targeted CCR6+ cells were efficiently inhibited from migrating into the bronchoalveoli. Finally, ADMET and physicochemical properties were well balanced and the preclinical package warranted progress in the clinic.

Facile synthesis of sterically hindered and electron-deficient secondary amides from isocyanates.

The big easy: The direct coupling of Grignard reagents to isocyanates provides a facile and robust solution for the synthesis of sterically hindered and electron-deficient secondary amides. The products are obtained in high yields without the need for excess reagents or chromatographic purification.

Discovery of the Potent, Selective, Orally Available CXCR7 Antagonist ACT-1004-1239.

The chemokine receptor CXCR7, also known as ACKR3, is a seven-transmembrane G-protein-coupled receptor (GPCR) involved in various pathologies such as neurological diseases, autoimmune diseases, and cancers. By binding and scavenging the chemokines CXCL11 and CXCL12, CXCR7 regulates their extracellular levels. From an original high-throughput screening campaign emerged hit 3 among others. The hit-to-lead optimization led to the discovery of a novel chemotype series exemplified by the trans racemic compound 11i. This series provided CXCR7 antagonists that block CXCL11- and CXCL12-induced ß-arrestin recruitment. Further structural modifications on the trisubstituted piperidine scaffold of 11i yielded compounds with high CXCR7 antagonistic activities and balanced ADMET properties. The effort described herein culminated in the discovery of ACT-1004-1239 (28f). Biological characterization of ACT-1004-1239 demonstrated that it is a potent, insurmountable antagonist. Oral administration of ACT-1004-1239 in mice up to 100 mg/kg led to a dose-dependent increase of plasma CXCL12 concentration.

Planar chiral asymmetric naphthalenediimide cyclophanes: synthesis, characterization and tunable FRET properties.

A series of planar chiral asymmetric naphthalenediimide (NDI) cyclophanes () consisting of two different NDIs interlinked by rigid meta-dimethylenebenzene spacers was synthesized. A modular synthetic strategy based on the dichloro cyclophane as common precursor gave a straightforward access to racemic mixtures of the NDI cyclophane dyes . In particular the substitution of both chlorine atoms of by tert-butylsulfanyl-, methoxy- and piperidinyl-groups provided racemic mixtures of the fluorescent NDI cyclophane dyes , and respectively. Fluorescence spectroscopy revealed chemically tuneable intramolecular FRET properties, as the spectral overlap between the emission of the unsubstituted NDI and the absorption of the core-substituted NDI subunit of the cyclophane could be adjusted by the core substituents. The racemic nature of the samples of cyclophanes , and in the case of the di-tert-butylsulfanyl functionalized cyclophane the enrichment of both enantiomers, was demonstrated by HPLC using a chiral stationary phase. The solid state structure of was determined by X-ray analysis. A periodic arrangement of both enantiomers of the planar chiral cyclophane in pillars such that NDI- and 2,6-core substituted NDI chromophores alternate periodically was observed.

Scalable Synthesis of Trifluoromethylated Imidazo-Fused N-Heterocycles Using TFAA and Trifluoroacetamide as CF3-Reagents.

A scalable synthesis of trifluoromethylated imidazo-fused N-heterocyles from heterocyclic benzylamines using TFAA as trifluoromethylating reagent is presented. The reaction proceeds via intermediate benzylic N-trifluoroacetamides followed by dehydrative cyclization to the products. To further broaden the scope and practicality, a new method for the preparation of benzylic N-trifluoroacetamides via alkylation of trifluoroacetamide with benzyl (pseudo)halides was developed. Both methods proceed under mild conditions, and their symbiosis provides access to a wide range of novel CF3-heterocycles.

Neuromuscular efficiency of the vastus lateralis and biceps femoris muscles in individuals with anterior cruciate ligament injuries.

OBJECTIVE: To analyze strength and integrated electromyography (IEMG) data in order to determine the neuromuscular efficiency (NME) of the vastus lateralis (VL) and biceps femoris (BF) muscles in patients with anterior cruciate ligament (ACL) injuries, during the preoperative and postoperative periods; and to compare the injured limb at these two times, using the non-operated limb as a control. METHODS: EMG data and BF and VL strength data were collected during three maximum isometric contractions in knee flexion and extension movements. The assessment protocol was applied before the operation and two months after the operation, and the NME of the BF and VL muscles was obtained. RESULTS: There was no difference in the NME of the VL muscle from before to after the operation. On the other hand, the NME of the BF in the non-operated limb was found to have increased, two months after the surgery. CONCLUSIONS: The NME provides a good estimate of muscle function because it is directly related to muscle strength and capacity for activation. However, the results indicated that two months after the ACL reconstruction procedure, at the time when loading in the open kinetic chain within rehabilitation protocols is usually started, the neuromuscular efficiency of the VL and BF had still not been reestablished.

OBJETIVO: Analisar a força e a integral da eletromiografia (IEMG) para obter a eficiência neuromuscular (ENM) dos músculos vasto lateral (VL) e bíceps femoral (BF) em pacientes com lesão de ligamento cruzado anterior (LCA) nas fases pré-operatória e pós-operatória, comparar o membro lesionado nos dois momentos e usar o membro não cirúrgico como controle. MÉTODOS: Foi feita a coleta de dados da EMG e da força de BF e VL durante três contrações isométricas máximas nos movimentos de flexão e extensão do joelho. O protocolo de avaliação foi aplicado nos momentos pré e pós-operatório (dois meses após a cirurgia) e obteve-se a ENM dos músculos VL e BF. RESULTADOS: Não foi encontrada diferença na ENM do músculo VL entre os momentos pré e pós-cirúrgico. Por outro lado, houve aumento da ENM do BF no membro não cirúrgico dois meses após a cirurgia. CONCLUSÕES: A ENM fornece boa estimativa da função muscular por estar diretamente relacionada à força e à capacidade de ativação dos músculos. Entretanto, os resultados apontam que dois meses após o procedimento de reconstrução do LCA, quando normalmente são iniciadas cargas em cadeia cinética aberta nos protocolos de reabilitação, a eficiência neuromuscular do VL e BF ainda não está restabelecida.

Synthesis of sterically hindered N-acylated amino acids from N-carboxyanhydrides.

Sterically hindered N-acyl, gem-disubstituted amino acids are easily prepared via the addition of organometallic reagents to N-carboxyanhydrides (NCA). The process tolerates a wide variety of functional groups and allows the synthesis of amide products not readily accessible by traditional acylation chemistry. The existence of an isocyanate intermediate was established by in situ IR spectroscopy.

Neuromuscular efficiency of the vastus lateralis and biceps femoris muscles in individuals with anterior cruciate ligament injuries / Eficiência neuromuscular dos músculos vasto lateral e bíceps femoral em indivíduos com lesão de ligamento cruzado anterior

OBJECTIVE: To analyze strength and integrated electromyography (IEMG) data in order to determine the neuromuscular efficiency (NME) of the vastus lateralis (VL) and biceps femoris (BF) muscles in patients with anterior cruciate ligament (ACL) injuries, during the preoperative and postoperative periods; and to compare the injured limb at these two times, using the non-operated limb as a control. METHODS: EMG data and BF and VL strength data were collected during three maximum isometric contractions in knee flexion and extension movements. The assessment protocol was applied before the operation and two months after the operation, and the NME of the BF and VL muscles was obtained. RESULTS: There was no difference in the NME of the VL muscle from before to after the operation. On the other hand, the NME of the BF in the non-operated limb was found to have increased, two months after the surgery. CONCLUSIONS: The NME provides a good estimate of muscle function because it is directly related to muscle strength and capacity for activation. However, the results indicated that two months after the ACL reconstruction procedure, at the time when loading in the open kinetic chain within rehabilitation protocols is usually started, the neuromuscular efficiency of the VL and BF had still not been reestablished. .

OBJETIVO: Analisar a força e a integral da eletromiografia (IEMG) para obter a eficiência neuromuscular (ENM) dos músculos vasto lateral (VL) e bíceps femoral (BF) em pacientes com lesão de ligamento cruzado anterior (LCA) nas fases pré-operatória e pós-operatória, comparar o membro lesionado nos dois momentos e usar o membro não cirúrgico como controle. MÉTODOS: Foi feita a coleta de dados da EMG e da força de BF e VL durante três contrações isométricas máximas nos movimentos de flexão e extensão do joelho. O protocolo de avaliação foi aplicado nos momentos pré e pós-operatório (dois meses após a cirurgia) e obteve-se a ENM dos músculos VL e BF. RESULTADOS: Não foi encontrada diferença na ENM do músculo VL entre os momentos pré e pós-cirúrgico. Por outro lado, houve aumento da ENM do BF no membro não cirúrgico dois meses após a cirurgia. CONCLUSÕES: A ENM fornece boa estimativa da função muscular por estar diretamente relacionada à força e à capacidade de ativação dos músculos. Entretanto, os resultados apontam que dois meses após o procedimento de reconstrução do LCA, quando normalmente são iniciadas cargas em cadeia cinética aberta nos protocolos de reabilitação, a eficiência neuromuscular do VL e BF ainda não está restabelecida. .