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1.
Nat Chem ; 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38565976

RESUMEN

Homochiral α-amino acids are widely used in pharmaceutical design as key subunits in chiral catalyst synthesis or as building blocks in synthetic biology. Many synthetic methods have been developed to access rare or unnatural variants by controlling the installation of the α-stereocentre. By contrast, and despite their importance, α-amino acids possessing ß-stereocentres are much harder to synthesize. Here we demonstrate an iridium-catalysed protocol that allows the direct upconversion of simple alkenes and glycine derivatives to give ß-substituted α-amino acids with exceptional levels of regio- and stereocontrol. Our method exploits the native directing ability of a glycine-derived N-H unit to facilitate Ir-catalysed enolization of the adjacent carbonyl. The resulting stereodefined enolate cross-couples with a styrene or α-olefin to install two contiguous stereocentres. The process offers very high levels of regio- and stereocontrol and occurs with complete atom economy. In broader terms, our reaction design offers a unique directing-group-controlled strategy for the direct stereocontrolled α-alkylation of carbonyl compounds, and provides a powerful approach for the synthesis of challenging contiguous stereocentres.

2.
J Med Chem ; 66(13): 9147-9160, 2023 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-37395055

RESUMEN

The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.


Asunto(s)
Antineoplásicos , Neoplasias Pulmonares , Neoplasias , Animales , Humanos , Antineoplásicos/farmacología , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias/tratamiento farmacológico , Diseño de Fármacos , Glicina/uso terapéutico , Mutación , Neoplasias Pulmonares/tratamiento farmacológico
3.
Chem Sci ; 13(37): 11183-11189, 2022 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-36320466

RESUMEN

Quaternary benzylic centers are accessed with high atom and step economy by Ir-catalyzed alkene hydroarylation. These studies provide unique examples of the use of non-polarized 1,1-disubstituted alkenes in branch selective Murai-type hydro(hetero)arylations. Detailed mechanistic studies have been undertaken, and these indicate that the first irreversible step is the demanding alkene carbometallation process. Structure-reactivity studies show that the efficiency of this is critically dependent on key structural features of the ligand. Computational studies have been undertaken to rationalize this experimental data, showing how more sterically demanding ligands reduce the reaction barrier via predistortion of the reacting intermediate. The key insight disclosed here will underpin the ongoing development of increasingly sophisticated branch selective Murai hydroarylations.

4.
ChemMedChem ; 15(24): 2513-2520, 2020 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-32812371

RESUMEN

Combined photochemical arylation, "nuisance effect" (SN Ar) reaction sequences have been employed in the design of small arrays for immediate deployment in medium-throughput X-ray protein-ligand structure determination. Reactions were deliberately allowed to run "out of control" in terms of selectivity; for example the ortho-arylation of 2-phenylpyridine gave five products resulting from mono- and bisarylations combined with SN Ar processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified.


Asunto(s)
Derivados del Benceno/síntesis química , Inhibidores Enzimáticos/síntesis química , Bibliotecas de Moléculas Pequeñas/síntesis química , Derivados del Benceno/metabolismo , Catálisis , Técnicas de Química Sintética/métodos , Complejos de Coordinación/química , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/metabolismo , Estudios de Factibilidad , Humanos , Paladio/química , Prueba de Estudio Conceptual , Unión Proteica , Piridinas/síntesis química , Piridinas/metabolismo , Pirofosfatasas/metabolismo , Pirrolidinonas/síntesis química , Pirrolidinonas/metabolismo , Bibliotecas de Moléculas Pequeñas/metabolismo , Hidrolasas Nudix
5.
Org Lett ; 21(22): 9232-9235, 2019 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-31696716

RESUMEN

The 4-π-photocyclization of a range of 1,2-dihydropyridazines is described, generating bicyclic 1,2-diazetidines in high yields on multigram scale. The key bicyclic 1,2-diazetidines are versatile synthetic intermediates and were easily converted into a range of novel derivatives, including functionalized 1,2-diazetidines, cyclobutenes, cyclobutanes, and 1,3-dienes.

6.
ACS Chem Biol ; 13(11): 3131-3141, 2018 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-30335946

RESUMEN

B-cell lymphoma 6 (BCL6) inhibition is a promising mechanism for treating hematological cancers but high quality chemical probes are necessary to evaluate its therapeutic potential. Here we report potent BCL6 inhibitors that demonstrate cellular target engagement and exhibit exquisite selectivity for BCL6 based on mass spectrometry analyses following chemical proteomic pull down. Importantly, a proteolysis-targeting chimera (PROTAC) was also developed and shown to significantly degrade BCL6 in a number of diffuse large B-cell lymphoma (DLBCL) cell lines, but neither BCL6 inhibition nor degradation selectively induced marked phenotypic response. To investigate, we monitored PROTAC directed BCL6 degradation in DLBCL OCI-Ly1 cells by immunofluorescence and discovered a residual BCL6 population. Analysis of subcellular fractions also showed incomplete BCL6 degradation in all fractions despite having measurable PROTAC concentrations, together providing a rationale for the weak antiproliferative response seen with both BCL6 inhibitor and degrader. In summary, we have developed potent and selective BCL6 inhibitors and a BCL6 PROTAC that effectively degraded BCL6, but both modalities failed to induce a significant phenotypic response in DLBCL despite achieving cellular concentrations.


Asunto(s)
Antineoplásicos/farmacología , Proteínas Proto-Oncogénicas c-bcl-6/antagonistas & inhibidores , Quinolonas/farmacología , Talidomida/análogos & derivados , Talidomida/farmacología , Proteínas Adaptadoras Transductoras de Señales , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Línea Celular Tumoral , Células HEK293 , Humanos , Ligandos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Péptido Hidrolasas/metabolismo , Unión Proteica , Proteolisis , Proteínas Proto-Oncogénicas c-bcl-6/química , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Quinolonas/síntesis química , Quinolonas/metabolismo , Talidomida/síntesis química , Talidomida/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo
8.
J Med Chem ; 60(10): 4386-4402, 2017 05 25.
Artículo en Inglés | MEDLINE | ID: mdl-28485934

RESUMEN

Inhibition of the protein-protein interaction between B-cell lymphoma 6 (BCL6) and corepressors has been implicated as a therapeutic target in diffuse large B-cell lymphoma (DLBCL) cancers and profiling of potent and selective BCL6 inhibitors are critical to test this hypothesis. We identified a pyrazolo[1,5-a]pyrimidine series of BCL6 binders from a fragment screen in parallel with a virtual screen. Using structure-based drug design, binding affinity was increased 100000-fold. This involved displacing crystallographic water, forming new ligand-protein interactions and a macrocyclization to favor the bioactive conformation of the ligands. Optimization for slow off-rate constant kinetics was conducted as well as improving selectivity against an off-target kinase, CK2. Potency in a cellular BCL6 assay was further optimized to afford highly selective probe molecules. Only weak antiproliferative effects were observed across a number of DLBCL lines and a multiple myeloma cell line without a clear relationship to BCL6 potency. As a result, we conclude that the BCL6 hypothesis in DLBCL cancer remains unproven.


Asunto(s)
Mapas de Interacción de Proteínas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Pirazoles/química , Pirazoles/farmacología , Piridinas/química , Piridinas/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Proteínas Proto-Oncogénicas c-bcl-6/antagonistas & inhibidores
9.
J Control Release ; 247: 73-85, 2017 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-28043863

RESUMEN

Irinotecan is used clinically for the treatment of colorectal cancer; however, its utility is limited by its narrow therapeutic index. We describe the use of a generation 5 l-lysine dendrimer that has been part-modified with a polyoxazoline as a drug delivery vehicle for improving the therapeutic index of SN-38, the active metabolite of irinotecan. By conjugating SN-38 to the dendrimer via different linker technologies we sought to vary the release rate of the drug to generate diverse pharmacokinetic profiles. Three conjugates with plasma release half-lives of 2.5h, 21h, and 72h were tested for efficacy and toxicity using a mouse SW620 xenograft model. In this model, the linker with a plasma release half-life of 21h achieved sustained SN-38 exposure in blood, above the target concentration. Control over the release rate of the drug from the linker, combined with prolonged circulation of the dendrimer, enabled administration of an efficacious dose of SN-38, achieving significant regression of the SW620 tumours. The conjugates with 2.5 and 72h release half-lives did not achieve an anti-tumour effect. Intraperitoneal dosing of the clinically used prodrug irinotecan produces high initial and local concentrations of SN-38, which are associated with gastrointestinal toxicity. Administration of the 21h release dendrimer conjugate did not produce a high initial Cmax of SN-38. Consequently, a marked reduction in gastrointestinal toxicity was observed relative to irinotecan treatment. Additional studies investigating the dose concentrations and dose scheduling showed that a weekly dosing schedule of 4mg SN-38/kg was the most efficacious regimen. After 4 doses at weekly intervals, the survival period of the mice extended beyond 70 days following the final dose. These extensive studies have allowed us to identify a linker, dose and dosing regimen for SN-38 conjugated to polyoxazoline-modified dendrimer that maximised efficacy and minimised adverse side effects.


Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Preparaciones de Acción Retardada/química , Dendrímeros/química , Animales , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/farmacocinética , Antineoplásicos Fitogénicos/uso terapéutico , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/farmacocinética , Camptotecina/uso terapéutico , Colon/efectos de los fármacos , Colon/patología , Neoplasias Colorrectales/patología , Femenino , Irinotecán , Ratones , Ratones Desnudos , Oxazoles/química , Ratas Wistar , Recto/efectos de los fármacos , Recto/patología
10.
ACS Omega ; 2(8): 4328-4332, 2017 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-31457724

RESUMEN

TC AC 28, 6-(1H-Indol-4-yl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-4-acetic acid methyl ester, has been synthesized on a near-gram scale in seven steps with notable improvements in the reported poor-yielding last two steps enabling this key chemical probe compound to be available for researchers.

11.
Adv Synth Catal ; 359(18): 3261-3269, 2017 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-30100832

RESUMEN

5-Phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-ones react under palladium- and visible light photoredox catalysis, in refluxing methanol, with aryldiazonium salts to afford the respective 5-(2-arylphenyl) analogues. With 2- or 4-fluorobenzenediazonium derivatives, both fluoroaryl- and methoxyaryl- products were obtained, the latter resulting from a SNAr on the fluorobenzenediazonium salt ("nuisance effect"). A computational DFT analysis of the palladium-catalysed and the palladium/ruthenium-photocalysed mechanism for the functionalization of benzodiazepines indicated that, in the presence of the photocatalyst, the reaction proceeds via a low-energy SET pathway avoiding the high-energy oxidative addition step in the palladium-only catalysed reaction pathway.

12.
ACS Med Chem Lett ; 7(12): 1118-1123, 2016 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-27994749

RESUMEN

Group I p21-activated kinase (PAK) inhibitors are indicated as important in cancer progression, but achieving high kinase selectivity has been challenging. A bis-anilino pyrimidine PAK1 inhibitor was identified and optimized through structure-based drug design to improve PAK1 potency and achieve high kinase selectivity, giving in vitro probe compound AZ13705339 (18). Reduction of lipophilicity to lower clearance afforded AZ13711265 (14) as an in vivo probe compound with oral exposure in mouse. Such probes will allow further investigation of PAK1 biology.

13.
J Org Chem ; 79(16): 7682-8, 2014 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-25050640

RESUMEN

A new synthetic route to 3-(heteroaryl) tetrahydropyrazolo[3,4-c]pyridines has been developed that uses the Suzuki-Miyaura cross-coupling of a triflate 6 with (hetero)aryl boronic acids or esters. Using Pd(OAc)2 and XPhos or an XPhos precatalyst, a diverse range of substituents at the C3 position of the tetrahydropyrazolo[3,4-c]pyridine skeleton were prepared. The use of pivaloyloxymethyl and benzyl protection also offers the potential to differentially functionalize the pyrazole and tetrahydropyridine nitrogens.


Asunto(s)
Compuestos de Bencilo/química , Paladio/química , Pirazoles/química , Pirazoles/síntesis química , Piridinas/química , Piridinas/síntesis química , Catálisis , Ésteres , Estructura Molecular
14.
J Med Chem ; 57(3): 970-86, 2014 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-24422550

RESUMEN

11ß-Hydroxysteroid dehydrogenase type 1 (11ß-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to yield 3, which had modest CNS penetration. More significant progress was achieved by changing the core to give 40, which combines good potency and CNS penetration. Compound 40 was dosed to diet-induced obese (DIO) mice and gave excellent target engagement in the liver and high free exposures of drug, both peripherally and in the CNS. However, no body weight reduction or effects on glucose or insulin were observed in this model. Similar data were obtained with a structurally diverse thiazole compound 51. This work casts doubt on the hypothesis that localized tissue modulation of 11ß-HSD1 activity alleviates metabolic syndrome.


Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Adamantano/síntesis química , Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/síntesis química , Síndrome Metabólico/tratamiento farmacológico , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , Adamantano/farmacocinética , Adamantano/farmacología , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Cristalografía por Rayos X , Ciclopropanos/síntesis química , Ciclopropanos/farmacocinética , Ciclopropanos/farmacología , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Grasas de la Dieta/administración & dosificación , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Insulina/sangre , Isoenzimas/antagonistas & inhibidores , Isoenzimas/química , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Síndrome Metabólico/metabolismo , Síndrome Metabólico/fisiopatología , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Modelos Moleculares , Pirazoles/síntesis química , Pirazoles/farmacocinética , Pirazoles/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacocinética , Tiazoles/farmacología
15.
J Med Chem ; 55(23): 10610-29, 2012 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-23116186

RESUMEN

A new series of pyrazinecarboxamide DGAT1 inhibitors was designed to address the need for a candidate drug with good potency, selectivity, and physical and DMPK properties combined with a low predicted dose in man. Rational design and optimization of this series led to the discovery of compound 30 (AZD7687), which met the project objectives for potency, selectivity, in particular over ACAT1, solubility, and preclinical PK profiles. This compound showed the anticipated excellent pharmacokinetic properties in human volunteers.


Asunto(s)
Acetatos/química , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Pirazinas/química , Acetatos/farmacocinética , Acetatos/farmacología , Animales , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Pirazinas/farmacocinética , Pirazinas/farmacología , Ratas , Solubilidad
16.
Bioorg Med Chem Lett ; 22(12): 3873-8, 2012 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-22608962

RESUMEN

A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.


Asunto(s)
Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Hipoglucemiantes/síntesis química , Oxadiazoles/síntesis química , Animales , Diabetes Mellitus/tratamiento farmacológico , Diacilglicerol O-Acetiltransferasa/metabolismo , Perros , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Semivida , Ensayos Analíticos de Alto Rendimiento , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Ligandos , Ratones , Obesidad/tratamiento farmacológico , Oxadiazoles/farmacocinética , Relación Estructura-Actividad Cuantitativa , Ratas
17.
J Med Chem ; 52(6): 1558-68, 2009 Mar 26.
Artículo en Inglés | MEDLINE | ID: mdl-19256504

RESUMEN

Inhibition of DGAT-1 is increasingly seen as an attractive mechanism with the potential for treatment of obesity and other elements of the metabolic syndrome. We report here a bicyclooctaneacetic acid derivative in the pyrimidinooxazine structural class of DGAT-1 inhibitors that has good potency, selectivity, and pharmacokinetic characteristics across a variety of species. This compound is an effective inhibitor of DGAT-1 in both intestinal and adipose tissue, which results in a reduction in body weight or body weight gain following oral administration in both mouse and rat models of dietary-induced obesity.


Asunto(s)
Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Oxazinas/farmacología , Pirimidinas/farmacología , Administración Oral , Animales , Peso Corporal/efectos de los fármacos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/tratamiento farmacológico , Ratas , Ratas Wistar , Espectrometría de Masa por Ionización de Electrospray
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