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1.
Circulation ; 148(2): 144-158, 2023 07 11.
Artículo en Inglés | MEDLINE | ID: mdl-37125593

RESUMEN

BACKGROUND: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design. METHODS: Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9. Following completion of nonclinical safety studies, MK-0616 was administered to healthy adult participants in a single rising-dose Phase 1 clinical trial designed to evaluate its safety, pharmacokinetics, and pharmacodynamics. In a multiple-dose trial in participants taking statins, MK-0616 was administered once daily for 14 days to characterize the safety, pharmacokinetics, and pharmacodynamics (change in low density lipoprotein cholesterol). RESULTS: MK-0616 displayed high affinity (Ki = 5pM) for PCSK9 in vitro and sufficient safety and oral bioavailability preclinically to enable advancement into the clinic. In Phase 1 clinical studies in healthy adults, single oral doses of MK-0616 were associated with >93% geometric mean reduction (95% CI, 84-103) of free, unbound plasma PCSK9; in participants on statin therapy, multiple-oral-dose regimens provided a maximum 61% geometric mean reduction (95% CI, 43-85) in low density lipoprotein cholesterol from baseline after 14 days of once-daily dosing of 20 mg MK-0616. CONCLUSIONS: This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need.


Asunto(s)
Anticolesterolemiantes , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hipercolesterolemia , Adulto , Humanos , Anticolesterolemiantes/efectos adversos , Colesterol , LDL-Colesterol , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Péptidos/uso terapéutico , Proproteína Convertasa 9/genética , Proproteína Convertasa 9/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo
2.
Bioorg Med Chem Lett ; 32: 127668, 2021 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-33161125

RESUMEN

Cholesteryl ester transfer protein (CETP) inhibitors reduce the transfer of cholesteryl esters from the high-density lipoprotein (HDL-C) to apolipoprotein such as VLDL/LDL, with exchange of triglycerides. Thus, this inhibition increases the HDL-C levels, which is believed to lower the risk for heart disease and stroke. We report here a series of CETP inhibitors based on the cyclic, bicyclic urea and sulfamide cores. These CETP inhibitors exemplified by 15, 31, and 45 demonstrated in vitro potency in inhibiting the CETP transfer activity, and 15, 31 showing in vivo efficacy to increase HDL-C levels in cynomolgus-CETP transgenic mice. The synthesis and biological evaluations of these CETP inhibitors are described.


Asunto(s)
Anticolesterolemiantes/síntesis química , Compuestos Bicíclicos con Puentes/química , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Sulfonamidas/química , Urea/análogos & derivados , Animales , Anticolesterolemiantes/metabolismo , Anticolesterolemiantes/uso terapéutico , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , HDL-Colesterol/sangre , Ciclización , Dislipidemias/tratamiento farmacológico , Dislipidemias/patología , Humanos , Ratones , Ratones Transgénicos , Relación Estructura-Actividad , Sulfonamidas/metabolismo , Sulfonamidas/uso terapéutico , Urea/metabolismo , Urea/uso terapéutico
3.
Bioorg Med Chem Lett ; 29(14): 1854-1858, 2019 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-31104995

RESUMEN

The derivatization of pharmaceuticals is a core activity in the discovery and development of new medicines. Late-stage functionalization via modern CH functionalization chemistry has emerged as a powerful technique with which to diversify advanced pharmaceutical intermediates. We report herein a case study in late-stage functionalization towards the development of a new class of indazole-based mineralocorticoid receptor antagonists (MRA). An effort to modify the electronics of the core indazole heterocycle inspired the use of modern CH borylation chemistry. New reactivity patterns were revealed and studied computationally. Ultimately, a de novo synthesis delivered a key 6-fluoroindazole compound 26, a potent MRA with excellent metabolic stability.


Asunto(s)
Desarrollo de Medicamentos/métodos , Indazoles/química , Antagonistas de Receptores de Mineralocorticoides/química , Estructura Molecular
4.
Bioorg Med Chem Lett ; 29(11): 1380-1385, 2019 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-30952592

RESUMEN

The parallel medicinal chemistry (PMC) was effectively applied to accelerate the optimization of diacylglycerol O-acyltransferase I (DGAT-1) inhibitors. Through a highly collaborative and iterative library design, synthesis and testing, a benzimidazole lead was rapidly and systematically advanced to a highly potent, selective and bioavailable DGAT1 inhibitor with the potential for further development.


Asunto(s)
Bencimidazoles/farmacología , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/química , Química Farmacéutica , Diacilglicerol O-Acetiltransferasa/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Relación Estructura-Actividad
5.
J Am Chem Soc ; 140(22): 6797-6800, 2018 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-29762027

RESUMEN

Targeting tryptophan is a promising strategy to achieve high levels of selectivity for peptide or protein modification. A chemoselective peptide modification method via photocatalytic tryptophan ß-position conjugation has been discovered. This transformation has good substrate scope for both peptide and Michael acceptor, and has good chemoselectivity versus other amino acid residues. The endogenous peptides, glucagon and GLP-1 amide, were both successfully conjugated at the tryptophan ß-position. Insulin was studied as a nontryptophan control molecule, resulting in exclusive B-chain C-terminal-selective decarboxylative conjugation. This transformation provides a novel approach toward peptide modification to support the discovery of new therapeutic peptides, protein labeling and bioconjugation.


Asunto(s)
Péptidos/química , Procesos Fotoquímicos , Proteínas/química , Triptófano/química , Catálisis/efectos de la radiación , Conformación Molecular
6.
Chem Soc Rev ; 46(6): 1760, 2017 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-28280821

RESUMEN

Correction for 'The medicinal chemist's toolbox for late stage functionalization of drug-like molecules' by Tim Cernak et al., Chem. Soc. Rev., 2016, 45, 546-576.

7.
Chem Soc Rev ; 45(3): 546-76, 2016 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-26507237

RESUMEN

The advent of modern C-H functionalization chemistries has enabled medicinal chemists to consider a synthetic strategy, late stage functionalization (LSF), which utilizes the C-H bonds of drug leads as points of diversification for generating new analogs. LSF approaches offer the promise of rapid exploration of structure activity relationships (SAR), the generation of oxidized metabolites, the blocking of metabolic hot spots and the preparation of biological probes. This review details a toolbox of intermolecular C-H functionalization chemistries with proven applicability to drug-like molecules, classified by regioselectivity patterns, and gives guidance on how to systematically develop LSF strategies using these patterns and other considerations. In addition, a number of examples illustrate how LSF approaches have been used to impact actual drug discovery and chemical biology efforts.

8.
Angew Chem Int Ed Engl ; 55(44): 13714-13718, 2016 10 24.
Artículo en Inglés | MEDLINE | ID: mdl-27690172

RESUMEN

The reactivity of a representative set of 17 organozinc pivalates with 18 polyfunctional druglike electrophiles (informers) in Negishi cross-coupling reactions was evaluated by high-throughput experimentation protocols. The high-fidelity scaleup of successful reactions in parallel enabled the isolation of sufficient material for biological testing, thus demonstrating the high value of these new solid zinc reagents in a drug-discovery setting and potentially for many other applications in chemistry. Principal component analysis (PCA) clearly defined the independent roles of the zincates and the informers toward druggable-space coverage.


Asunto(s)
Compuestos Organometálicos/química , Piridinas/síntesis química , Zinc/química , Ensayos Analíticos de Alto Rendimiento , Estructura Molecular , Análisis de Componente Principal , Piridinas/química
9.
Angew Chem Int Ed Engl ; 53(19): 4802-6, 2014 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-24677697

RESUMEN

The direct CH functionalization of heterocycles has become an increasingly valuable tool in modern drug discovery. However, the introduction of small alkyl groups, such as methyl, by this method has not been realized in the context of complex molecule synthesis since existing methods rely on the use of strong oxidants and elevated temperatures to generate the requisite radical species. Herein, we report the use of stable organic peroxides activated by visible-light photoredox catalysis to achieve the direct methyl-, ethyl-, and cyclopropylation of a variety of biologically active heterocycles. The simple protocol, mild reaction conditions, and unique tolerability of this method make it an important tool for drug discovery.


Asunto(s)
Compuestos Heterocíclicos/química , Catálisis , Oxidación-Reducción , Fotoquímica
10.
J Fluoresc ; 21(6): 2133-41, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21750892

RESUMEN

The electronic absorption, fluorescence excitation and emission spectra, and fluorescence quantum yields of novel fused thienobenzofurans, including thieno[3,2-b][1]benzofuran (1), [1]benzothieno[3,2-b]furan (2), and [1]benzothieno[3,2-b][1]benzofuran (3), were recorded in fourteen solvents of different polarities at room temperature. Compound 2 was not fluorescent. Experimental ground-state dipole moments of compounds 1-3 were measured in benzene at 298 K and compared with the corresponding theoretical dipole moment values. The solvent effects on the electronic absorption and fluorescence spectra of these thienobenzofurans were quantitatively investigated by means of solvatochromic correlations based on the Kawski-Chamma-Viallet and McRae equations. A weak negative solvatochromic behavior was found for these compounds, showing that their dipole moments are slightly lower in the excited singlet-state than in the ground-state. Kamlet-Abboud-Taft multiparameter relationships were also established for electronic absorption and fluorescence wavenumbers, and fluorescence quantum yields in most solvents, demonstrating the occurrence of specific solute-solvent interactions.


Asunto(s)
Benzofuranos/química , Fluorescencia , Teoría Cuántica , Estructura Molecular , Solventes/química , Espectrometría de Fluorescencia , Espectrofotometría Ultravioleta
11.
ACS Med Chem Lett ; 12(3): 337-342, 2021 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-33738059

RESUMEN

An integrated workflow has been established that enables the synthesis, purification, and subsequent biological testing of compound libraries on a microgram scale. This approach utilizes mass directed preparative HPLC in conjunction with charged aerosol detection (CAD) to generate solutions of investigational compounds at high purity and standardized concentrations, facilitating high fidelity biological testing. This new workflow successfully delivered libraries of histone deacetylase (HDAC) inhibitors that afforded biological data consistent with that obtained from standard scale parallel medicinal chemistry techniques. The advantages of this new approach to library synthesis include greatly reduced material requirements and amenability to high-throughput experimentation.

12.
J Med Chem ; 64(18): 13215-13258, 2021 09 23.
Artículo en Inglés | MEDLINE | ID: mdl-34375108

RESUMEN

Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.


Asunto(s)
Anticolesterolemiantes/uso terapéutico , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Enfermedad Coronaria/tratamiento farmacológico , Oxazolidinonas/uso terapéutico , Animales , Anticolesterolemiantes/síntesis química , Anticolesterolemiantes/farmacocinética , Anticolesterolemiantes/toxicidad , Perros , Humanos , Macaca mulatta , Ratones Endogámicos C57BL , Estructura Molecular , Oxazolidinonas/síntesis química , Oxazolidinonas/farmacocinética , Oxazolidinonas/toxicidad , Ratas Wistar , Relación Estructura-Actividad
13.
ACS Med Chem Lett ; 9(7): 773-777, 2018 Jul 12.
Artículo en Inglés | MEDLINE | ID: mdl-30034617

RESUMEN

Recent visible-light photoredox catalyzed C(sp3)-C(sp2) cross-coupling provides a novel transformation to potentially enable the synthesis of medicinal chemistry targets. Here, we report a profiling study of photocatalytic C(sp3)-C(sp2) cross-coupling, both decarboxylative coupling and cross-electrophile coupling, with 18 pharmaceutically relevant aryl halides by using either Kessil lamp or our newly developed integrated photoreactor. Integrated photoreactor accelerates reaction rate and improves reaction success rate. Cross-electrophile coupling gives higher success rate with broad substrate scope on alkyl halides than that of the decarboxylative coupling. In addition, a successful application example on a discovery program demonstrates the efficient synthesis of medicinal chemistry targets via photocatalytic C(sp3)-C(sp2) cross-coupling by using our integrated photoreactor.

14.
ACS Cent Sci ; 3(6): 647-653, 2017 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-28691077

RESUMEN

Photocatalysis for organic synthesis has experienced an exponential growth in the past 10 years. However, the variety of experimental procedures that have been reported to perform photon-based catalyst excitation has hampered the establishment of general protocols to convert visible light into chemical energy. To address this issue, we have designed an integrated photoreactor for enhanced photon capture and catalyst excitation. Moreover, the evaluation of this new reactor in eight photocatalytic transformations that are widely employed in medicinal chemistry settings has confirmed significant performance advantages of this optimized design while enabling a standardized protocol.

15.
J Med Chem ; 60(9): 3594-3605, 2017 05 11.
Artículo en Inglés | MEDLINE | ID: mdl-28252959

RESUMEN

Miniaturization and parallel processing play an important role in the evolution of many technologies. We demonstrate the application of miniaturized high-throughput experimentation methods to resolve synthetic chemistry challenges on the frontlines of a lead optimization effort to develop diacylglycerol acyltransferase (DGAT1) inhibitors. Reactions were performed on ∼1 mg scale using glass microvials providing a miniaturized high-throughput experimentation capability that was used to study a challenging SNAr reaction. The availability of robust synthetic chemistry conditions discovered in these miniaturized investigations enabled the development of structure-activity relationships that ultimately led to the discovery of soluble, selective, and potent inhibitors of DGAT1.


Asunto(s)
Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Cromatografía Liquida , Espectrometría de Masas , Espectroscopía de Protones por Resonancia Magnética
16.
J Med Chem ; 49(11): 3060-3, 2006 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-16722624

RESUMEN

Alendronate derivatives were evaluated as potential prodrugs for the osteoporosis drug alendronate sodium in an attempt to enhance the systemic exposure after oral administration. An investigation of the chemical behavior of alendronate derivatives led to development of practical synthetic strategies and prediction of each structural class's prodrug potential. Pharmacokinetic studies of N-myristoylalendronic acid revealed that 25% have been converted in vivo after i.v. administration in rat, providing an important proof-of-concept for this strategy.


Asunto(s)
Alendronato/análogos & derivados , Alendronato/síntesis química , Conservadores de la Densidad Ósea/síntesis química , Profármacos/síntesis química , Alendronato/farmacocinética , Animales , Densidad Ósea , Conservadores de la Densidad Ósea/farmacocinética , Osteoporosis/tratamiento farmacológico , Profármacos/farmacocinética , Ratas , Relación Estructura-Actividad
17.
Chem Sci ; 7(4): 2604-2613, 2016 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-28660032

RESUMEN

Major new advances in synthetic chemistry methods are typically reported using simple, non-standardized reaction substrates, and reaction failures are rarely documented. This makes the evaluation and choice of a synthetic method difficult. We report a standardized complex molecule diagnostic approach using collections of relevant drug-like molecules which we call chemistry informer libraries. With this approach, all chemistry results, successes and failures, can be documented to compare and evolve synthetic methods. To aid in the visualization of chemistry results in drug-like physicochemical space we have used an informatics methodology termed principal component analysis. We have validated this method using palladium- and copper-catalyzed reactions, including Suzuki-Miyaura, cyanation and Buchwald-Hartwig amination.

18.
ACS Med Chem Lett ; 7(3): 261-5, 2016 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-26985312

RESUMEN

Using the collective body of known (CETP) inhibitors as inspiration for design, a structurally novel series of tetrahydroquinoxaline CETP inhibitors were discovered. An exemplar from this series, compound 5, displayed potent in vitro CETP inhibition and was efficacious in a transgenic cynomologus-CETP mouse HDL PD (pharmacodynamic) assay. However, an undesirable metabolic profile and chemical instability hampered further development of the series. A three-dimensional structure of tetrahydroquinoxaline inhibitor 6 was proposed from (1)H NMR structural studies, and this model was then used in silico for the design of a new class of compounds based upon an indoline scaffold. This work resulted in the discovery of compound 7, which displayed potent in vitro CETP inhibition, a favorable PK-PD profile relative to tetrahydroquinoxaline 5, and dose-dependent efficacy in the transgenic cynomologus-CETP mouse HDL PD assay.

19.
Science ; 347(6217): 49-53, 2015 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-25554781

RESUMEN

At the forefront of new synthetic endeavors, such as drug discovery or natural product synthesis, large quantities of material are rarely available and timelines are tight. A miniaturized automation platform enabling high-throughput experimentation for synthetic route scouting to identify conditions for preparative reaction scale-up would be a transformative advance. Because automated, miniaturized chemistry is difficult to carry out in the presence of solids or volatile organic solvents, most of the synthetic "toolkit" cannot be readily miniaturized. Using palladium-catalyzed cross-coupling reactions as a test case, we developed automation-friendly reactions to run in dimethyl sulfoxide at room temperature. This advance enabled us to couple the robotics used in biotechnology with emerging mass spectrometry-based high-throughput analysis techniques. More than 1500 chemistry experiments were carried out in less than a day, using as little as 0.02 milligrams of material per reaction.


Asunto(s)
Ensayos Analíticos de Alto Rendimiento/métodos , Nanopartículas , Nanotecnología/métodos , Preparaciones Farmacéuticas/síntesis química , Biotecnología , Catálisis , Espectrometría de Masas , Paladio/química , Robótica/métodos
20.
Eur J Pharmacol ; 740: 410-6, 2014 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-24769414

RESUMEN

Inhibition of cholesteryl ester transfer protein (CETP) has been vigorously pursued as a potential therapy to treat patients who are at an elevated risk for coronary artery disease. Anacetrapib, a novel CETP inhibitor, has been shown clinically to raise HDL cholesterol and reduce LDL cholesterol when provided as monotherapy or when co-administered with a statin. Preclinically, the effects of anacetrapib on the functionality and composition of HDL have been extensively studied. In contrast, the effects of anacetrapib on other parameters related to lipoprotein metabolism and cardiovascular risk have been difficult to explore. The aim of the present investigation was to evaluate the effects of anacetrapib in rhesus macaques and to compare these to effects reported in dyslipidemic humans. Our results from two separate studies show that administration of anacetrapib (150 mg/kg q.d. for 10 days) to rhesus macaques results in alterations in CETP activity (reduced by more than 70%) and HDL cholesterol (increased by more than 110%) which are similar to those reported in dyslipidemic humans. Levels of LDL cholesterol were reduced by more than 60%, an effect slightly greater than what has been observed clinically. Treatment with anacetrapib in this model was also found to lead to statistically significant reductions in plasma PCSK9 and to reduce cholesterol excursion in the combined chylomicron and remnant lipoprotein fraction isolated from plasma by fast protein liquid chromatography. Collectively, these data suggest that rhesus macaques may be a useful translational model to study the mechanistic effects of CETP inhibition.


Asunto(s)
Anticolesterolemiantes/farmacología , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Oxazolidinonas/farmacología , Animales , Apolipoproteínas/sangre , Proteínas de Transferencia de Ésteres de Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Macaca mulatta , Masculino , Proproteína Convertasas/sangre , Serina Endopeptidasas/sangre , Triglicéridos/sangre
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