RESUMO
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.
Assuntos
Anticolesterolemiantes , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , Adulto , Humanos , Anticolesterolemiantes/efeitos adversos , Colesterol , LDL-Colesterol , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Peptídeos/uso terapêutico , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismoRESUMO
An effective strategy has been developed for the photoredox-catalyzed decarboxylative addition of cyclic amino acids to both vinylogous amides and esters leading to uniquely substituted heterocycles. The additions take place exclusively trans to the substituent present on the dihydropyridone ring affording stereochemical control about the new carbon-carbon bond. These reactions are operationally simplistic and afford the desired products in good to excellent isolated yields.
RESUMO
Previously disclosed benzimidazole-based DGAT1 inhibitors containing a cyclohexane carboxylic acid moiety suffer from isomerization at the alpha position of the carboxylic acid group, generating active metabolites which exhibit DGAT1 inhibition comparable to the corresponding parent compounds. In this report, we describe the design, synthesis and profiling of benzimidazole-based DGAT1 inhibitors with a [3.1.0] bicyclohexane carboxylic acid moiety. Our results show that single isomer 3A maintains in vitro and in vivo inhibition against DGAT1. In contrast to previous lead compounds, 3A does not undergo isomerization during in vitro hepatocyte incubation study or in vivo mouse study.
Assuntos
Benzimidazóis/química , Ácidos Carboxílicos/química , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Inibidores Enzimáticos/química , Animais , Benzimidazóis/metabolismo , Ácidos Carboxílicos/metabolismo , Cromatografia Líquida de Alta Pressão , Cicloexanonas/química , Diacilglicerol O-Aciltransferase/metabolismo , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/metabolismo , Hepatócitos/química , Hepatócitos/metabolismo , Humanos , Concentração Inibidora 50 , Isomerismo , Espectrometria de Massas , Camundongos , RatosRESUMO
The evolution of a scalable process for the preparation of methylcyclobutanol-pyridyl ether 1 is described. Key aspects of this development including careful control of the stereochemistry, elimination of chromatography, and application to kilogram-scale synthesis are addressed.
Assuntos
Ciclobutanos/química , Éteres/química , Cromatografia Gasosa , Desenho de Fármacos , Éteres/síntese química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The development of a practical asymmetric total synthesis of the potent HIV-1 integrase inhibitor 5 is described. Key transformations include construction of the naphthridine core in a highly efficient manner followed by cyclization of the 8-membered ring. Control of the atropisomers of intermediates and final compound 5 is also described.
Assuntos
Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/efeitos dos fármacos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Ciclização , Inibidores de Integrase de HIV/química , Naftiridinas/química , Espectroscopia de Prótons por Ressonância MagnéticaRESUMO
Novel potent and selective 5,6,5- and 5,5,6-tricyclic pyrrolidine dipeptidyl peptidase IV (DPP-4) inhibitors were identified. Structure-activity relationship (SAR) efforts focused on improving the intrinsic DPP-4 inhibition potency, increasing protease selectivity, and demonstrating clean ion channel and cytochrome P450 profiles while trying to achieve a pharmacokinetic profile suitable for once weekly dosing in humans.
Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Descoberta de Drogas , Pirrolidinas/farmacologia , Animais , Cristalografia por Raios X , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Cães , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
A series of novel substituted-[(3R)-amino-2-(2,5-difluorophenyl)]tetrahydro-2H-pyran analogs have been prepared and evaluated as potent, selective and orally active DPP-4 inhibitors. These efforts lead to the discovery of a long acting DPP-4 inhibitor, omarigliptin (MK-3102), which recently completed phase III clinical development and has been approved in Japan.
Assuntos
Amidas/química , Inibidores da Dipeptidil Peptidase IV/química , Compostos Heterocíclicos com 2 Anéis/química , Piranos/química , Sulfonamidas/química , Animais , Sítios de Ligação , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Cães , Meia-Vida , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Piranos/síntese química , Piranos/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
The synthesis, SAR, binding affinities and pharmacokinetic profiles are described for a series of cyclohexane-based prolylcarboxypeptidase (PrCP) inhibitors discovered by high throughput screening. Compounds show high levels of ex vivo target engagement in mouse plasma 20 h post oral dose.
Assuntos
Carboxipeptidases/antagonistas & inibidores , Cicloexanos/química , Cicloexanos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Animais , Cicloexanos/farmacocinética , Descoberta de Drogas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Obesidade/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Cholesteryl ester transfer protein inhibitors are an important class of compounds designed to treat hypocholesterolemia and prevent cardiovascular disease. Anacetrapib (MK-0859) is currently in phase III trials for the treatment of elevated cholesterol levels and prevention of cardiovascular disease. In order to further support the development of anacetrapib, we prepared [M + 6]MK-0859, which was required in support of an absolute bioavailability study of the active pharmaceutical ingredient (API). Additional support included the synthesis of an internal standard [M + 13] and three stable isotope labeled metabolites, which were used to analyze clinical samples, and [(14) C]MK-0859 to support drug metabolism studies.
Assuntos
Anticolesterolemiantes/síntese química , Oxazolidinonas/síntese química , Compostos Radiofarmacêuticos/síntese química , Radioisótopos de Carbono/química , Marcação por IsótopoRESUMO
The solution-based gram-scale synthesis of complex and highly potent proprotein convertase subtilisin-like/kexin type 9 (PCSK9) inhibitor 1 is presented. Construction of Northern fragment 2, followed by stepwise installation of Eastern 3, Southern 4, and Western 5 fragments, provided macrocyclic precursor 19. This intermediate was cross-linked via an intramolecular azide-alkyne click reaction, which preceded macrolactamization to afford the core framework of compound 1. Finally, coupling with poly(ethylene glycol) side-chain-based 6 gave the PCSK9 inhibitor 1.
Assuntos
Pró-Proteína Convertase 9RESUMO
An economical and simple flow mixer based on magnetically driven agitation in a tube (MDAT) is reported. Mixing via MDAT compared favorably to both Tee and multilaminar mixers at low flow and was successfully used to screen and optimize two challenging organometallic reactions at low temperature without clogging or the need for high dilution.
Assuntos
Compostos Organometálicos/química , Compostos Organometálicos/síntese química , Simulação por Computador , Desenho de Equipamento/instrumentação , Microfluídica/instrumentação , Estrutura Molecular , TemperaturaRESUMO
Development of a practical synthesis of MK-7009, a 20-membered [corrected] macrocycle, is described. A variety of ring-closing strategies were evaluated, including ring-closing metathesis, intermolecular palladium-catalyzed cross-couplings, and macrolactamization. Ring closure via macrolactamization was found to give the highest yields under relatively high reaction concentrations. Optimization of the ring formation step and the synthesis of key intermediates en route to MK-7009 are reported.
Assuntos
Técnicas de Química Sintética/métodos , Indóis/química , Indóis/síntese química , Lactamas/química , Compostos Macrocíclicos/química , Catálise , Ciclização , Ciclopropanos , Hidrogenação , Isoindóis , Lactamas Macrocíclicas , Leucina/análogos & derivados , Paládio/química , Prolina/análogos & derivados , SulfonamidasRESUMO
Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. Starting from second-generation lead structures such as 2, we were able to refine these structures to obtain extremely potent bi- and tricyclic PCSK9 inhibitor peptides. Optimized molecules such as 44 demonstrated sufficient oral bioavailability to maintain therapeutic levels in rats and cynomolgus monkeys after dosing with an enabled formulation. We demonstrated target engagement and LDL lowering in cynomolgus monkeys essentially identical to those observed with the clinically approved, parenterally dosed antibodies. These molecules represent the first report of highly potent and orally bioavailable macrocyclic peptide PCSK9 inhibitors with overall profiles favorable for potential development as once-daily oral lipid-lowering agents. In this manuscript, we detail the design criteria and multiparameter optimization of this novel series of PCSK9 inhibitors.
Assuntos
Inibidores de PCSK9/farmacologia , Peptídeos Cíclicos/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Macaca fascicularis , Estrutura Molecular , Inibidores de PCSK9/química , Inibidores de PCSK9/farmacocinética , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
A one-pot, high-yielding iodination of hydroxypyridines and hydroxyquinolines is described. The iodination proceeds under mild conditions, and the products are obtained in high yield without the need for chromatographic purification. In addition, the iodination works on both 2- and 4-hydroxypyridines and -hydroxyquinolines.
Assuntos
Piridinas/química , Cromatografia Líquida de Alta Pressão , Halogenação , Hidroxiquinolinas/química , Estrutura MolecularRESUMO
An effective strategy has been developed for the preparation of 3-alkoxymethyl-pyrazolo[3,4-b]pyridines, compounds that are currently not readily accessible by existing synthetic methods. Further manipulation of these compounds allows for access to 3-alkoxymethyl-pyrazolo[3,4-b]pyridines with a variety of substitution patterns as well as 3-aminomethyl-pyrazolo[3,4-b]pyridines.
Assuntos
Pirazóis/síntese química , Piridinas/síntese química , Cinética , Pirazóis/química , Piridinas/químicaRESUMO
ß-Aminoacrylates are reactive intermediates that are useful building blocks in synthesis. General methods for their preparation typically afford α and ß disubstitution patterns or ß only. Molecules with only α-substituents (ß-hydrogen) are much less well-known. A chemoselective reductive tautomerization of α-cyanoacetates, using DIBAL-H, has been developed to access these valuable synthons. α,ß-Unsaturated cyanoacetates and α-cyanoketones can, also, be selectively reduced via this methodology. A series of heterocycles were prepared using these ß-enamino carbonyl compounds.
RESUMO
The discovery of novel 4-hydroxy-2-(heterocyclic)pyrimidine-5-carboxamide inhibitors of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD) is described. These are potent, selective, orally bioavailable across several species, and active in stimulating erythropoiesis. Mouse and rat studies showed hematological changes with elevations of plasma EPO and circulating reticulocytes following single oral dose administration, while 4-week q.d. po administration in rat elevated hemoglobin levels. A major focus of the optimization process was to decrease the long half-life observed in higher species with early compounds. These efforts led to the identification of 28 (MK-8617), which has advanced to human clinical trials for anemia.
Assuntos
Anemia/tratamento farmacológico , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Piridazinas/farmacologia , Pirimidinas/farmacologia , Administração Oral , Anemia/enzimologia , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Piridazinas/administração & dosagem , Piridazinas/química , Pirimidinas/administração & dosagem , Pirimidinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.
Assuntos
Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/farmacologia , Piridonas/síntese química , Piridonas/farmacologia , Animais , Área Sob a Curva , Cães , Relação Dose-Resposta a Droga , Desenho de Fármacos , Integrase de HIV/efeitos dos fármacos , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/farmacocinética , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/genética , Humanos , Modelos Moleculares , Pró-Fármacos , Piridonas/farmacocinética , RatosRESUMO
[reaction: see text] An effective strategy has been developed for the rapid and efficient preparation of ortho-nitrostyrenes, which can be converted to unsymmetrical 2,2'-biindoles. A unique condensation of these 2,2'-biindoles with (dimethylamino)-acetaldehyde diethyl acetal affords the indolocarbazole ring system of the tjipanazole aglycon alkaloids in three synthetic steps and good to excellent overall yield. The first total synthesis of the tjipanazole glycoside alkaloids B and E is also discussed.
Assuntos
Alcaloides/síntese química , Carbazóis/química , Glicosídeos/química , Indóis/química , Alcaloides/química , Carbazóis/síntese química , Glicosídeos/síntese química , Indóis/síntese química , Estereoisomerismo , Estirenos/químicaRESUMO
[reaction: see text] A concise and efficient synthesis of the novel indol-2-yl-1H-quinolin-2-one ring system found in the potent and selective KDR kinase inhibitors 1-3 is presented.