RESUMEN
Nipecotic acid is considered to be one of the most potent inhibitors of neuronal and glial-aminobutyric acid (GABA) uptake in vitro. Due to its hydrophilic nature, nipecotic acid does not readily cross the blood-brain barrier (BBB). Large neutral amino acids (LAT1)-knotted nipecotic acid prodrug was designed and synthesized with the aim to enhance the BBB permeation by the use of carrier-mediated transport. The synthesized prodrug was tested in animal models of Pentylenetetrazole (PTZ)-induced convulsions in mice. Further pain studies were carried out followed by neurotoxicity estimation by writhing and rota-rod test respectively. HPLC data suggests that the synthesized prodrug has improved penetration through BBB. Nipecotic acid-L-serine ester prodrug with considerable anti-epileptic activity, and the ability to permeate the BBB has been successfully synthesized. Graphical Abstract.
Asunto(s)
Barrera Hematoencefálica/metabolismo , Ácidos Nipecóticos/química , Ácidos Nipecóticos/síntesis química , Profármacos/química , Profármacos/síntesis química , Serina/química , Serina/síntesis química , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Transporte Biológico/efectos de los fármacos , Ésteres/síntesis química , Ésteres/química , Ésteres/farmacología , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Ratones , Ácidos Nipecóticos/farmacología , Pentilenotetrazol/síntesis química , Pentilenotetrazol/química , Pentilenotetrazol/farmacología , Profármacos/farmacología , Convulsiones/tratamiento farmacológicoRESUMEN
A 6-step enantioselective synthesis of (2S,3R)-3-alkyl/alkenylglutamates, including the biologically significant amino acid, (2S,3R)-3-methylglutamate, protected for Fmoc SPPS, is reported. Overall yields range from 52-65%. Key to the success of these syntheses was the development of a high-yielding 2-step synthesis of Fmoc Garner's aldehyde followed by a Horner-Wadsworth-Emmons reaction to give the corresponding Fmoc Garner's enoate in a 94% yield. The diastereoselective 1,4-addition of lithium dialkylcuprates to the Fmoc Garner's enoate was explored. Significant decomposition occurred when using lithium diethylcuprate and conditions previously reported for the 1,4-addition of lithium dialkylcuprates to Boc or Cbz-protected Garner's enoate. An optimization study of this reaction resulted in a robust set of conditions that addressed the shortcomings of previously reported conditions. Under these conditions, highly diastereoselective (> 20:1 in most cases) 1,4-addition reactions of lithium dialkyl/dialkenylcuprates to the Fmoc Garner's enoate were achieved in 76-99% yield. The resulting 1,4-addition products were easily converted into the Fmoc-(2S,3R)-3-alkyl/alkenylglutamates in two steps.
Asunto(s)
Aldehídos/química , Glutamatos/síntesis química , 3-O-Metilglucosa/síntesis química , Aminoácidos/síntesis química , Fluorenos , Serina/análogos & derivados , Serina/síntesis química , EstereoisomerismoRESUMEN
The synthesis of 19 compounds derived from l-serine and analogs of p-substituted cinnamic acid is reported. Oxazolines 9 and oxazoles 10 have high antitubercular activity with Minimum Inhibitory Concentration (MIC) of 0.7812-25.0 µg/mL (3.21-100.3 µM), against two strains of Mycobacterium tuberculosis sensitive to first-line drugs Isoniazid (INH), Rifampicin (RIF), Ethambutol (EMB), Pyrazinamide (PZE) (H37Rv) and a clinical isolate resistant to INH, RIF and EMB (G122). The cytotoxic evaluation shows that oxazoles have low activity, finding viability>96% against the VERO cell line. The results show these compounds could be considered as future alternatives for antitubercular treatment.
Asunto(s)
Antineoplásicos/farmacología , Antituberculosos/farmacología , Serina/análogos & derivados , Serina/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Antituberculosos/síntesis química , Antituberculosos/química , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Farmacorresistencia Bacteriana Múltiple , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Mycobacterium tuberculosis/efectos de los fármacos , Serina/síntesis química , Serina/química , Células VeroRESUMEN
Specific spin labeling allows the site-selective investigation of biomolecules by EPR and DNP enhanced NMR spectroscopy. A novel spin labeling strategy for commercially available Fmoc-amino acids is developed. In this approach, the PROXYL spin label is covalently attached to the hydroxyl side chain of three amino acids hydroxyproline (Hyp), serine (Ser) and tyrosine (Tyr) by a simple three-step synthesis route. The obtained PROXYL containing building-blocks are N-terminally protected by the Fmoc-protection group, which makes them applicable for the use in solid-phase peptide synthesis (SPPS). This approach allows the insertion of the spin label at any desired position during SPPS, which makes it more versatile than the widely used post synthetic spin labeling strategies. For the final building-blocks, the radical activity is proven by EPR. DNP enhanced solid-state NMR experiments employing these building-blocks in a TCE solution show enhancement factors of up to 26 for 1 H and 13 C (1 Hâ13 C cross-polarization). To proof the viability of the presented building-blocks for insertion of the spin label during SPPS the penta-peptide Acetyl-Gly-Ser(PROXYL)-Gly-Gly-Gly was synthesized employing the spin labeled Ser building-block. This peptide could successfully be isolated and the spin label activity proved by EPR and DNP NMR measurements, showing enhancement factors of 12.1±0.1 for 1 H and 13.9±0.5 for 13 C (direct polarization).
Asunto(s)
Aminoácidos/síntesis química , Fluorenos/síntesis química , Oligopéptidos/síntesis química , Pirrolidinas/síntesis química , Técnicas de Síntesis en Fase Sólida/métodos , Marcadores de Spin/síntesis química , Espectroscopía de Resonancia por Spin del Electrón , Hidroxiprolina/síntesis química , Espectroscopía de Protones por Resonancia Magnética , Serina/síntesis química , Tirosina/síntesis químicaRESUMEN
Peptide macrocycles are widely utilized in the development of high affinity ligands, including stapled α-helices. The linear rigidity of a 1,3-diynyl linkage provides an optimal distance (7â Å) between ß-carbons of the i,i+4 amino acid side chains, thus suggesting its utility in stabilizing α-helical structures. Here, we report the development of an on-resin strategy for an intramolecular Glaser reaction between two alkyne-terminated side chains by using copper chloride, an essential bpy-diol ligand, and diisopropylethylamine at room temperature. The efficiency of this ligation was illustrated by the synthesis of (i,i+4)-, (i,i+5)-, (i,i+6)-, and (i,i+7)-stapled BCL-9 α-helical peptides using the unnatural amino acid propargyl serine. Overall, this procedurally simple method relies on inexpensive and widely available reagents to generate low molecular weight 23-, 26-, 29-, and 32-membered peptide macrocycles.
Asunto(s)
Técnicas de Química Sintética/métodos , Compuestos Macrocíclicos/síntesis química , Péptidos Cíclicos/síntesis química , Serina/análogos & derivados , Alquinos/síntesis química , Alquinos/química , Técnicas de Química Sintética/economía , Cobre/química , Ligandos , Compuestos Macrocíclicos/química , Modelos Moleculares , Péptidos Cíclicos/química , Estructura Secundaria de Proteína , Serina/síntesis química , Factores de TiempoRESUMEN
Synthesis and evaluation of new scaffold phenylisoserine derivatives connected with the essential functional groups against SARS CoV 3CL protease are described. The phenylisoserine backbone was found by simulation on GOLD software and the structure activity relationship study of phenylisoserine derivatives gave SK80 with an IC50 value of 43µM against SARS CoV 3CL R188I mutant protease.
Asunto(s)
Inhibidores de Proteasas/farmacología , Serina/análogos & derivados , Proteínas Virales/antagonistas & inhibidores , Proteasas 3C de Coronavirus , Cisteína Endopeptidasas/genética , Cisteína Endopeptidasas/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Serina/síntesis química , Serina/química , Serina/farmacología , Relación Estructura-Actividad , Proteínas Virales/genética , Proteínas Virales/metabolismoRESUMEN
Synthesis of serine derivatives having the essential functional groups for the inhibitor of SARS 3CL protease and evaluation of their inhibitory activities using SARS 3CL R188I mutant protease are described. The lead compounds, functionalized serine derivatives, were designed based on the tetrapeptide aldehyde and Bai's cinnamoly inhibitor, and additionally performed with simulation on GOLD softwear. Structure activity relationship studies of the candidate compounds were given reasonable inhibitors ent-3 and ent-7k against SARS 3CL R188I mutant protease. These inhibitors showed protease selectivity and no cytotoxicity.
Asunto(s)
Diseño de Fármacos , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Serina/análogos & derivados , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/enzimología , Bibliotecas de Moléculas Pequeñas/farmacología , Proteínas Virales/antagonistas & inhibidores , Muerte Celular/efectos de los fármacos , Proteasas 3C de Coronavirus , Cisteína Endopeptidasas/metabolismo , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteasas/química , Serina/síntesis química , Serina/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad , Proteínas Virales/metabolismoRESUMEN
The synthesis of the uncommon dihydropyrazinone ring was accomplished by a two-step one pot process taking advantage of the ring rearrangement of N-acylated morpholine acetal derived from serine under acidic treatment in the presence of 2,6-lutidine. The mechanism involves an N-acyl iminium intermediate resulting from morpholine acetal ring opening, which occurs after a nucleophilic attack of the amino acid nitrogen atom to the acetal carbonyl atom. X-Ray diffraction analysis of the dihydropyrazinone, which may be exploited as a constrained Xaa-Ser dipeptide isostere, showed a planar assembly and the internal side-chain in axial orientation with respect to the cyclic molecular scaffold.
Asunto(s)
Acetales/química , Dipéptidos/química , Morfolinas/química , Pirazinas/química , Acetales/síntesis química , Acilación , Cristalografía por Rayos X , Dipéptidos/síntesis química , Modelos Moleculares , Morfolinas/síntesis química , Pirazinas/síntesis química , Piridinas/síntesis química , Piridinas/química , Serina/síntesis química , Serina/químicaRESUMEN
We report methods for the synthesis of polypeptides that are fully functionalized with desirable phosphorylcholine, PC, groups. Because of the inherent challenges in the direct incorporation of the PC group into α-amino acid N-carboxyanhydride (NCA) monomers, we developed a synthetic approach that combined functional NCA polymerization with efficient postpolymerization modification. While poly(L-phosphorylcholine serine) was found to be unstable upon synthesis, we successfully prepared poly(L-phosphorylcholine homoserine) with controlled chain lengths and found these to be water-soluble with disordered chain conformations.
Asunto(s)
Homoserina/análogos & derivados , Péptidos/síntesis química , Fosforilcolina/análogos & derivados , Serina/análogos & derivados , Homoserina/síntesis química , Péptidos/química , Fosforilcolina/síntesis química , Polimerizacion , Serina/síntesis químicaRESUMEN
Advances in the development of efficient peptide ligation methods have enabled the total synthesis of complex proteins to be successfully undertaken. Recently, a Ser/Thr ligation has emerged as a new tool in synthetic protein chemistry. The chemoselective reaction between an N-terminal serine or threonine of an unprotected peptide segment and a C-terminal salicylaldehyde ester of another unprotected peptide segment gives rise to an N,O-benzylidene acetal linked product, which upon acidolysis produces a native peptide bond at the site of ligation. Ser/Thr ligation has been used for the synthesis of the human erythrocyte acylphosphatase protein and MUC1 glycopeptide segments, semisynthesis of peptoid/PEG-RNase S protein hybrids, and cyclic peptide synthesis including cyclic tetrapeptides, cyclomontanin B, yunnanin C, mahafacyclin B, and daptomycin.
Asunto(s)
Péptidos/síntesis química , Proteínas/síntesis química , Serina/química , Treonina/química , Aldehídos/síntesis química , Aldehídos/química , Secuencia de Aminoácidos , Animales , Ciclización , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Péptidos/química , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/química , Proteínas/química , Serina/síntesis química , Treonina/síntesis químicaRESUMEN
The identification of fast, chemoselective bond-forming reactions is one of the major contemporary challenges in chemistry. The requirements of the native chemical ligation - an N-terminal cysteine and C-terminal thioesters - have encouraged a search for alternative amide-forming ligation reactions. Among successful alternatives to native chemical ligation, are the α-ketoacid-hydroxylamine ligation with 5-oxaproline and, serine/threonine ligation, and potassium acyltrifluoroborate (KAT) ligation. In addition, the KAT ligation, along with the non-amide forming alkyne-azide ligation, is very useful for synthetic conjugations. All of these recent ligation methods were applied to synthesize different proteins, and have allowed chemists to incorporate unnatural amino acids, or to modify the peptide backbone.
Asunto(s)
Péptidos/síntesis química , Proteínas/síntesis química , Alquinos/síntesis química , Alquinos/química , Secuencia de Aminoácidos , Azidas/síntesis química , Azidas/química , Modelos Moleculares , Datos de Secuencia Molecular , Péptidos/química , Prolina/análogos & derivados , Prolina/síntesis química , Prolina/química , Proteínas/química , Serina/síntesis química , Serina/química , Treonina/síntesis química , Treonina/químicaRESUMEN
Chemical synthesis of proteins, especially those with post-translational modifications, has offered new opportunities to study the protein structure-function relationship. In the past four years, we have developed the serine/threonine ligation (STL), which involves the chemoselective reaction between peptide salicylaldehyde esters and peptides with N-terminal serine or threonine. The method has been successfully applied to the synthesis of both linear and cyclic peptides/proteins.
Asunto(s)
Técnicas de Química Sintética/métodos , Serina/síntesis química , Treonina/síntesis química , Ácido Anhídrido Hidrolasas/metabolismo , Secuencia de Aminoácidos , Eritrocitos/enzimología , Ésteres/química , Datos de Secuencia Molecular , Mucina-1/metabolismo , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/química , Serina/química , Treonina/química , AcilfosfatasaRESUMEN
d-Amino acids can play important roles as specific biosynthetic building blocks required by organisms or act as regulatory molecules. Consequently, amino acid racemases that catalyze the formation of d-amino acids are potential therapeutic targets. Serine racemase catalyzes the reversible formation of d-serine (a modulator of neurotransmission) from l-serine, while proline racemase (an essential enzymatic and mitogenic protein in trypanosomes) catalyzes the reversible conversion of l-proline to d-proline. We show the substrate-product analogue α-(hydroxymethyl)serine is a modest, linear mixed-type inhibitor of serine racemase from Schizosaccharomyces pombe (Ki=167±21mM, Ki'=661±81mM, cf. Km=19±2mM). The bicyclic substrate-product analogue of proline, 7-azabicyclo[2.2.1]heptan-7-ium-1-carboxylate is a weak inhibitor of proline racemase from Clostridium sticklandii, giving only 29% inhibition at 142.5mM. However, the more flexible bicyclic substrate-product analogue tetrahydro-1H-pyrrolizine-7a(5H)-carboxylate is a noncompetitive inhibitor of proline racemase from C. sticklandii (Ki=111±15mM, cf. Km=5.7±0.5mM). These results suggest that substrate-product analogue inhibitors of racemases may only be effective when the active site is capacious and/or plastic, or when the inhibitor is sufficiently flexible.
Asunto(s)
Isomerasas de Aminoácido/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Prolina/farmacología , Racemasas y Epimerasas/antagonistas & inhibidores , Serina/análogos & derivados , Isomerasas de Aminoácido/metabolismo , Clostridium sticklandii/enzimología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Modelos Moleculares , Estructura Molecular , Prolina/análogos & derivados , Prolina/química , Racemasas y Epimerasas/metabolismo , Schizosaccharomyces/enzimología , Serina/síntesis química , Serina/química , Serina/farmacología , Relación Estructura-ActividadRESUMEN
A metal-free and 4-methyl aniline mediated method for the oxidative C-C bond cleavage has been developed. The reaction proceeds in air using molecular oxygen as the oxidant, affording one-carbon shortened esters in moderate to good yields within a short time. Moreover, it provides a model reaction for the highly enantioselective synthesis of (D)-serine esters by combining with a l-proline catalyzed Mannich reaction.
Asunto(s)
Aldehídos/química , Aminoácidos/síntesis química , Compuestos de Anilina/química , Aminoácidos/química , Oxidación-Reducción , Oxígeno/química , Serina/análogos & derivados , Serina/síntesis química , EstereoisomerismoRESUMEN
Aminopeptidase N (APN/CD13) is one of the essential proteins for tumour invasion, angiogenesis and metastasis as it is over-expressed on the surface of different tumour cells. Based on our previous work that L-isoserine dipeptide derivatives were potent APN inhibitors, we designed and synthesized L-isoserine tripeptide derivatives as APN inhibitors. Among these compounds, one compound 16l (IC50 = 2.51 ± 0.2 µM) showed similar inhibitory effect compared with control compound Bestatin (IC50 = 6.25 ± 0.4 µM) and it could be used as novel lead compound for the APN inhibitors development as anticancer agents in the future.
Asunto(s)
Antígenos CD13/antagonistas & inhibidores , Diseño de Fármacos , Oligopéptidos/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Serina/análogos & derivados , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Antígenos CD13/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Humanos , Células K562 , Modelos Moleculares , Conformación Molecular , Oligopéptidos/síntesis química , Oligopéptidos/química , Inhibidores de Proteasas/química , Serina/síntesis química , Serina/química , Serina/farmacología , Relación Estructura-ActividadRESUMEN
In the presence of 1.1 equiv of PhMe(2)Si-Bpin, 5 equiv of CsF, and 20 mol % of TsOH·H(2)O, precursors of N-Boc-imines can be converted into the corresponding α-aryl or α-alkenyl glycine derivatives under gaseous CO(2) in moderate-to-high yields with a single operation. α-Isobutenyl glycine thus obtained can be further derivatized into various types of α-amino acids including N-Boc-leucine, serine, and glycine derivatives in short steps.
Asunto(s)
Aminoácidos/síntesis química , Iminas/química , Aminoácidos/química , Dióxido de Carbono , Glicina/síntesis química , Glicina/química , Indicadores y Reactivos , Leucina/síntesis química , Leucina/química , Estructura Molecular , Serina/síntesis química , Serina/química , EstereoisomerismoRESUMEN
A series of novel pyrazole peptidomimetics was synthesized from 3-aryl-1-arylmethyl-1H-pyrazole-5-carboxylic acid and amino acid ester. Structures of the compounds were characterized by means of IR, (1)H NMR and mass spectroscopy. Compounds 5e and 5k suppress effectively the growth of A549 lung cancer cells. Preliminary research on the mechanism of action showed that the inhibition might perform through combination of apoptosis, autophagy and cell cycle arrest.
Asunto(s)
Antineoplásicos/síntesis química , Pirazoles/química , Pirazoles/síntesis química , Serina/análogos & derivados , Antineoplásicos/química , Antineoplásicos/toxicidad , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Ácidos Carboxílicos/química , Línea Celular Tumoral , Puntos de Control de la Fase G1 del Ciclo Celular/efectos de los fármacos , Humanos , Peptidomiméticos , Pirazoles/toxicidad , Serina/síntesis química , Serina/química , Serina/toxicidad , Relación Estructura-ActividadRESUMEN
N(α)-Lauryl-O-(ß-D-xylopyranosyl)-L-serinamide (Xyl-Ser-C12) was synthesized as a saccharide primer to obtain oligosaccharides of glycosaminoglycan using the glycan biosynthetic potential of mouse osteosarcoma FBJ-S1 cells and Chinese hamster ovary (CHO) cells. The glycosylated products secreted into the culture medium were collected and analyzed by liquid chromatography-mass spectrometry and glycosidase digestion. The structure of the Xyl-Ser-C12 derivatives was investigated. Several glycosaminoglycan-type oligosaccharides, such as GalNAc-(GlcA-GlcNAc)(n)-GlcA-Gal-Gal-Xyl-Ser-C12, were detected, and identified as intermediates of the biosynthesis of heparan sulfate glycosaminoglycans. Xyl-Ser-C12 exhibited greater acceptor activity for the glycosylation of glycosaminoglycan-type oligosaccharides than p-nitrophenyl-ß-D-xylopyranoside.
Asunto(s)
Glicósidos/síntesis química , Lipopéptidos/síntesis química , Oligosacáridos/biosíntesis , Serina/análogos & derivados , Animales , Células CHO , Supervivencia Celular , Células Cultivadas , Cricetinae , Glicósido Hidrolasas/metabolismo , Glicósidos/química , Glicósidos/metabolismo , Glicosilación , Lipopéptidos/química , Lipopéptidos/metabolismo , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Oligosacáridos/química , Oligosacáridos/metabolismo , Serina/síntesis química , Serina/química , Serina/metabolismoRESUMEN
D-Serine is a physiological coagonist of the N-methyl D-aspartate (NMDA) type of glutamate receptor-a key excitatory neurotransmitter receptor in the brain. D-Serine appears to be a part of the synapse through a variety of transporters located on both neurons and astrocytes. The development of 99mTc radiolabeled amino acid based radiopharmaceuticals for imaging a variety of tumors has found to be useful in diagnostic imaging. Diethylene triamine penta acetic acid (DTPA) is one of the most well-known chelating reagent for the production of stable complexes with various heavy metal ions. We have synthesized [DTPA-bis(D-ser)] in 90% yield and analyzed the chelate by spectroscopic techniques. The DBDSC chelate binds to 99mTc with high efficiency at ambient temperature. The resulting chelate is stable under physiological conditions (37oC, pH=7.4) for at least 24 h after radiocomplexation. The receptor binding studies of 99mTc-[DTPA-bis(D-ser)] in established lung adeno carcinoma A549 exhibited Kd value to be 26nM. A549 Tumor in athymic mice was accumulated in the γ-images. The major accumulation of the radiotracer was observed in tumor, followed by kidneys. 99mTc-[DTPA-bis(D-ser)] has promising utility as SPECT-radiopharmaceutical.
Asunto(s)
Quelantes/síntesis química , Neoplasias/diagnóstico por imagen , Compuestos de Organotecnecio/síntesis química , Radiofármacos/síntesis química , Serina/síntesis química , Pentetato de Tecnecio Tc 99m/síntesis química , Tomografía Computarizada de Emisión de Fotón Único , Animales , Quelantes/farmacocinética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias/metabolismo , Compuestos de Organotecnecio/farmacocinética , Conejos , Ensayo de Unión Radioligante , Radiofármacos/farmacocinética , Serina/farmacocinética , Pentetato de Tecnecio Tc 99m/farmacocinéticaRESUMEN
A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth. Further optimization of our lead series led to the discovery of proline derivatives 37 (XL541) and 38 which had similar efficacy as our first generation analogues at significantly lower doses. Analogue 37 displayed excellent pharmacokinetics and oral exposure in multiple species.