RESUMEN
The identification of clinical candidate LY3522348 (compound 23) is described. LY3522348 is a highly selective, oral dual inhibitor of human ketohexokinase isoforms C and A (hKHK-C, hKHK-A). Optimization began with highly efficient (S)-2-(2-methylazetidin-1-yl)-6-(1H-pyrazol-4-yl)-4-(trifluoromethyl)nicotinonitrile (3). Efforts focused on developing absorption, distribution, metabolism, potency, and in vitro safety profiles to support oral QD dosing in patients. Structure-based design leveraged vectors for substitution of the pyrazole ring, which provided an opportunity to interact with several different proximal amino acid residues in the protein. LY3522348 displayed a robust pharmacodynamic response in a mouse model of fructose metabolism and was advanced into clinical trials.
Asunto(s)
Fructoquinasas , Ratones , Animales , HumanosRESUMEN
Among the numerous antibody-drug conjugate (ADC) clinical candidates, one of the most prevalent types utilizes the interchain cysteines in antibodies to conjugate auristatin via a maleimide-containing linker. In this class of ADCs, there are a paucity of systematic studies characterizing how IgG subclass influences the biophysical properties and in vivo pharmacokinetics of the ADC molecules. In the current investigation, we studied cysteine-conjugated ADCs using a model system consisting of human IgG1, IgG2, and IgG4 antibodies with the same variable region. Our findings identified some unforeseen differences among the three ADCs. Drug conjugation profiling by LC-MS revealed that 50% of inter heavy-light chain disulfide bonds are disrupted to conjugate drugs in IgG1 antibody while only 10% in IgG2 antibody and 20% in IgG4 antibody. The solution behavior of the ADCs was interrogated in concentrating experiments and diffusion interaction parameter measurements. We found that drug conjugation affected the solution property of the three antibodies differently, with the IgG2-based ADC having the most increased propensity to aggregate. Rat PK studies using a sensitive LC-MS-based bioanalytical method showed that the IgG1-based ADC has poor peripheral linker-payload stability while the IgG2- and IgG4-based ADCs are stable. The conjugate stability of the IgG2-based ADC was further confirmed in a cynomolgus monkey PK study. Overall, the IgG2-based ADC exhibited the best PK/conjugate stability but also the most deterioration in stability among the three ADCs. Our findings provide important information and present multifactorial considerations for the selection of IgG subclass during ADC drug discovery when employing stochastic cysteine conjugation.
Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Cisteína/química , Inmunoconjugados/farmacocinética , Inmunoglobulina G/farmacología , Región Variable de Inmunoglobulina/farmacología , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/química , Células CHO , Cricetulus , Estabilidad de Medicamentos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/química , Inmunoglobulina G/química , Región Variable de Inmunoglobulina/química , Macaca fascicularis , Masculino , Ratas , SolubilidadRESUMEN
The RAS-RAF-MEK-MAPK cascade is an essential signaling pathway, with activation typically mediated through cell surface receptors. The kinase inhibitors vemurafenib and dabrafenib, which target oncogenic BRAF V600E, have shown significant clinical efficacy in melanoma patients harboring this mutation. Because of paradoxical pathway activation, both agents were demonstrated to promote growth and metastasis of tumor cells with RAS mutations in preclinical models and are contraindicated for treatment of cancer patients with BRAF WT background, including patients with KRAS or NRAS mutations. In order to eliminate the issues associated with paradoxical MAPK pathway activation and to provide therapeutic benefit to patients with RAS mutant cancers, we sought to identify a compound not only active against BRAF V600E but also wild type BRAF and CRAF. On the basis of its superior in vitro and in vivo profile, compound 13 was selected for further development and is currently being evaluated in phase I clinical studies.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Pirimidinas/química , Pirimidinas/farmacología , Proteínas ras/metabolismo , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Disponibilidad Biológica , Línea Celular Tumoral/efectos de los fármacos , Técnicas de Química Sintética , Perros , Femenino , Semivida , Humanos , Masculino , Ratones Desnudos , Terapia Molecular Dirigida , Mutación , Compuestos de Fenilurea/síntesis química , Compuestos de Fenilurea/farmacocinética , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas c-raf/metabolismo , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas Sprague-Dawley , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas ras/genéticaRESUMEN
A 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole (4) is a central structural feature of the Strychnos alkaloid minfiensine (1) and akuammiline alkaloids such as vincorine (5) and echitamine (6). A cascade catalytic asymmetric Heck-iminium cyclization was developed that rapidly provides 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazoles in high enantiomeric purity. Two sequences were developed for advancing 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazole 27 to (+)-minfiensine. In our first-generation approach, a reductive Heck cyclization was employed to form the fifth ring of (+)-minfiensine. In a second more concise total synthesis, an intramolecular palladium-catalyzed ketone enolate vinyl iodide coupling was employed to construct the final ring of (+)-minfiensine. This second-generation total synthesis of enantiopure (+)-minfiensine was accomplished in 6.5% overall yield and 15 steps from 1,2-cyclohexanedione and anisidine 13. A distinctive feature of this sequence is the use of palladium-catalyzed reactions to form all carbon-carbon bonds in the transformation of these simple precursors to (+)-minfiensine.
Asunto(s)
Alcaloides/síntesis química , Carbazoles/síntesis química , Iminas/química , Strychnos/química , Alcaloides/química , Carbazoles/química , Cristalografía por Rayos X , Ciclización , Cicloparafinas/química , Compuestos Epoxi/química , Iones/química , Modelos Moleculares , Estructura Molecular , EstereoisomerismoRESUMEN
A catalytic asymmetric method for the chemical synthesis of alkaloids containing the 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole (1) moiety is reported and verified by the enantioselective total synthesis of (+)-minfiensine (4). The central step in this total synthesis is the sequential catalytic asymmetric Heck-N-acyliminium ion cyclization of dienyl carbamate triflate 10, prepared in six steps from 1,2-cyclohexanedione, to give enantiopure 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazole (12) in 75% yield. Iminoethano-9H-carbazole 12 is transformed in six steps to dienyl iodide 17, which undergoes diastereoselective intramolecular Heck cyclization to form pentacyclic intermediate 18. In eight additional steps, this latter intermediate is transformed to (+)-minfiensine (4).
Asunto(s)
Alcaloides/síntesis química , Carbazoles/síntesis química , Ciclización , Iminas/química , Estereoisomerismo , Strychnos/químicaRESUMEN
[reaction: see text]. A series of quinone monoacetals bearing electron-withdrawing groups was treated with diethyl malonate and other bifunctional nucleophiles in the presence of KO-t-Bu in THF. Reactions of ethyl 3-nitropropionate or diethyl malonate resulted in single conjugate addition adducts. When ethyl acetoacetate was used as a nucleophile, bridged bicyclic products were obtained in good yields. The regiochemistry of conjugate addition was dependent on the quinone monoacetal substitution.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Ciclohexanos/química , Cristalografía por Rayos X , Ciclohexenos , Conformación Molecular , Estructura Molecular , EstereoisomerismoRESUMEN
A series of strained bi- and tricyclic amides has been shown to be unusually sensitive to cleavage of the C-N bond adjacent to the amide moiety. This bond undergoes facile breaking when subjected to treatment with H2/Pd(OH)2, MeI, and DDQ. In each case, the reaction is highly regioselective and mainly results in breaking the C-N bond that deviates the farthest from its natural planar state. Preliminary experiments that bear on the mechanisms of these reactions are described.
Asunto(s)
Amidas/química , Lactamas/química , Modelos Moleculares , Conformación MolecularRESUMEN
Total syntheses of alkaloid 251F (1), a natural product detected from the skin extracts of the dendrobatid frog species Minyobates bombetes, and its racemic 3-desmethyl derivative (2) are reported. A Diels-Alder reaction initiated both syntheses and established four consecutive stereogenic centers. Important to the synthesis of 2 was a first-generation ozonolysis/olefination/aldol strategy to convert a [2.2.1] bicyclic acid to the [3.3.0]bicyclooctane diquinane 4b. Further elaboration to an appropriate keto azide allowed for a key intramolecular Schmidt reaction to deliver the tricyclic core of the target molecule. In a second-generation approach, a tandem ring-opening/ring-closing metathesis reaction effected an overall [2.2.1] --> [3.3.0] skeletal rearrangement to deliver diquinane 4a. In similar fashion, 4a was manipulated to an appropriate keto azide, and an intramolecular Schmidt reaction generated the core cyclic architecture of 251F.
Asunto(s)
Alcaloides/química , Alcaloides/síntesis química , Indolizinas/síntesis química , Cristalografía por Rayos X , Indolizinas/química , Espectroscopía de Resonancia Magnética , Conformación Molecular , Estructura Molecular , EstereoisomerismoRESUMEN
The dendrobatid alkaloid (-)-251F was synthesized. The key steps of the synthesis were (1) an asymmetric Diels-Alder reaction to establish four of the necessary stereocenters in the target, (2) a ring-opening/ring-closing metathesis reaction to establish a key [3.3.0] bicyclic intermediate, and (3) an intramolecular Schmidt reaction.
Asunto(s)
Alcaloides/síntesis química , Animales , Anuros/metabolismoRESUMEN
[reaction: see text] A double diastereotopic differentiation strategy on a phosphonoacetate template is described. The approach utilizes Rh(2)(OAc)(4)-catalyzed intramolecular cyclopropanation (ICP) employing the (R)-pantolactone auxiliary in the ester functionality of the phosphonoacetate. The olefinic diastereofacial selectivity is governed by inherent electronic and steric interactions in the reacting carbene intermediate, while the group selectivity is dictated by the chiral auxiliary. This approach is being developed as an effective method to access bicyclic P-chiral phosphonates.