RÉSUMÉ
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.
Sujet(s)
Proprotéine convertase 9RÉSUMÉ
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.
Sujet(s)
Anticholestérolémiants , Inhibiteurs de l'hydroxyméthylglutaryl-CoA réductase , Hypercholestérolémie , Adulte , Humains , Anticholestérolémiants/effets indésirables , Cholestérol , Cholestérol LDL , Inhibiteurs de l'hydroxyméthylglutaryl-CoA réductase/usage thérapeutique , Peptides/usage thérapeutique , Proprotéine convertase 9/génétique , Proprotéine convertase 9/métabolisme , Récepteurs aux lipoprotéines LDL/génétique , Récepteurs aux lipoprotéines LDL/métabolismeRÉSUMÉ
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.
RÉSUMÉ
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.
Sujet(s)
Inhibiteurs de PCSK9/pharmacologie , Peptides cycliques/pharmacologie , Administration par voie orale , Animaux , Biodisponibilité , Cristallographie aux rayons X , Macaca fascicularis , Structure moléculaire , Inhibiteurs de PCSK9/composition chimique , Inhibiteurs de PCSK9/pharmacocinétique , Peptides cycliques/composition chimique , Peptides cycliques/pharmacocinétique , Rats , Relation structure-activitéRÉSUMÉ
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.
Sujet(s)
Benzimidazoles/composition chimique , Acides carboxyliques/composition chimique , Diacylglycerol O-acyltransferase/antagonistes et inhibiteurs , Antienzymes/composition chimique , Animaux , Benzimidazoles/métabolisme , Acides carboxyliques/métabolisme , Chromatographie en phase liquide à haute performance , Cyclohexanones/composition chimique , Diacylglycerol O-acyltransferase/métabolisme , Antienzymes/analyse , Antienzymes/métabolisme , Hépatocytes/composition chimique , Hépatocytes/métabolisme , Humains , Concentration inhibitrice 50 , Isomérie , Spectrométrie de masse , Souris , RatsRÉSUMÉ
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.
Sujet(s)
Cyclobutanes/composition chimique , Éthers/composition chimique , Chromatographie en phase gazeuse , Conception de médicament , Éthers/synthèse chimique , Stéréoisomérie , Relation structure-activitéRÉSUMÉ
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.
Sujet(s)
Anémie/traitement médicamenteux , Découverte de médicament , Antienzymes/pharmacologie , Hypoxia-inducible factor-proline dioxygenases/antagonistes et inhibiteurs , Pyridazines/pharmacologie , Pyrimidines/pharmacologie , Administration par voie orale , Anémie/enzymologie , Animaux , Relation dose-effet des médicaments , Antienzymes/administration et posologie , Antienzymes/composition chimique , Humains , Hypoxia-inducible factor-proline dioxygenases/métabolisme , Souris , Souris de lignée C57BL , Modèles moléculaires , Structure moléculaire , Pyridazines/administration et posologie , Pyridazines/composition chimique , Pyrimidines/administration et posologie , Pyrimidines/composition chimique , Rats , Rat Sprague-Dawley , Relation structure-activitéRÉSUMÉ
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.
RÉSUMÉ
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.
Sujet(s)
Inhibiteurs de l'intégrase du VIH/synthèse chimique , Inhibiteurs de l'intégrase du VIH/pharmacologie , Intégrase du VIH/effets des médicaments et des substances chimiques , Spectroscopie par résonance magnétique du carbone-13 , Cyclisation , Inhibiteurs de l'intégrase du VIH/composition chimique , Naphtyridines/composition chimique , Spectroscopie par résonance magnétique du protonRÉSUMÉ
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.
Sujet(s)
Dipeptidyl peptidase 4/métabolisme , Inhibiteurs de la dipeptidyl-peptidase IV/pharmacologie , Découverte de médicament , Pyrrolidines/pharmacologie , Animaux , Cristallographie aux rayons X , Inhibiteurs de la dipeptidyl-peptidase IV/synthèse chimique , Inhibiteurs de la dipeptidyl-peptidase IV/composition chimique , Chiens , Relation dose-effet des médicaments , Humains , Modèles moléculaires , Structure moléculaire , Pyrrolidines/synthèse chimique , Pyrrolidines/composition chimique , Rats , Relation structure-activitéRÉSUMÉ
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.
Sujet(s)
Amides/composition chimique , Inhibiteurs de la dipeptidyl-peptidase IV/composition chimique , Composés hétérobicycliques/composition chimique , Pyrannes/composition chimique , Sulfonamides/composition chimique , Animaux , Sites de fixation , Dipeptidyl peptidase 4/composition chimique , Dipeptidyl peptidase 4/métabolisme , Inhibiteurs de la dipeptidyl-peptidase IV/synthèse chimique , Inhibiteurs de la dipeptidyl-peptidase IV/pharmacocinétique , Chiens , Période , Composés hétérobicycliques/synthèse chimique , Composés hétérobicycliques/pharmacocinétique , Simulation de docking moléculaire , Structure tertiaire des protéines , Pyrannes/synthèse chimique , Pyrannes/pharmacocinétique , Rats , Relation structure-activitéRÉSUMÉ
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.
Sujet(s)
Inhibiteurs de l'intégrase du VIH/synthèse chimique , Inhibiteurs de l'intégrase du VIH/pharmacologie , Pyridones/synthèse chimique , Pyridones/pharmacologie , Animaux , Aire sous la courbe , Chiens , Relation dose-effet des médicaments , Conception de médicament , Intégrase du VIH/effets des médicaments et des substances chimiques , Intégrase du VIH/métabolisme , Inhibiteurs de l'intégrase du VIH/pharmacocinétique , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/effets des médicaments et des substances chimiques , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/enzymologie , VIH-1 (Virus de l'Immunodéficience Humaine de type 1)/génétique , Humains , Modèles moléculaires , Promédicaments , Pyridones/pharmacocinétique , RatsRÉSUMÉ
1,1-Disubstituted aryl cyclopropyl nitriles are useful moieties in biologically active compounds and provide access to a range of cyclopropyl derivatives. Herein, we describe the development of a palladium-catalyzed α-arylation of cyclopropyl, cyclobutyl, and cyclopentyl nitriles that affords these functional groups in one step from a variety of aryl bromides in good to excellent yields. Furthermore, we demonstrate the transformation of aryl cyclopropyl nitriles into aryl trifluoromethyl cyclopropanes.
Sujet(s)
Cyclopropanes/composition chimique , Nitriles/composition chimique , Palladium/composition chimique , Catalyse , Cyclopropanes/synthèse chimique , Structure moléculaire , Nitriles/synthèse chimiqueRÉSUMÉ
We report the discovery of a novel series of DGAT1 inhibitors in the benzimidazole class with a piperdinyl-oxy-cyclohexanecarboxylic acid moiety. This novel series possesses significantly improved selectivity against the A2A receptor, no ACAT1 off-target activity at 10 µM, and higher aqueous solubility and free fraction in plasma as compared to the previously reported pyridyl-oxy-cyclohexanecarboxylic acid series. In particular, 5B was shown to possess an excellent selectivity profile by screening it against a panel of more than 100 biological targets. Compound 5B significantly reduces lipid excursion in LTT in mouse and rat, demonstrates DGAT1 mediated reduction of food intake and body weight in mice, is negative in a 3-strain Ames test, and appears to distribute preferentially in the liver and the intestine in mice. We believe this lead series possesses significant potential to identify optimized compounds for clinical development.
RÉSUMÉ
In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.
Sujet(s)
Diabète de type 2/traitement médicamenteux , Inhibiteurs de la dipeptidyl-peptidase IV/pharmacologie , Composés hétérobicycliques/pharmacologie , Hypoglycémiants/pharmacologie , Pyrannes/pharmacologie , Animaux , Inhibiteurs de la dipeptidyl-peptidase IV/synthèse chimique , Inhibiteurs de la dipeptidyl-peptidase IV/pharmacocinétique , Inhibiteurs de la dipeptidyl-peptidase IV/toxicité , Composés hétérobicycliques/synthèse chimique , Composés hétérobicycliques/pharmacocinétique , Composés hétérobicycliques/toxicité , Humains , Hypoglycémiants/synthèse chimique , Hypoglycémiants/pharmacocinétique , Hypoglycémiants/toxicité , Pyrannes/synthèse chimique , Pyrannes/pharmacocinétique , Pyrannes/toxicité , Relation structure-activitéRÉSUMÉ
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.
Sujet(s)
Anticholestérolémiants/synthèse chimique , Oxazolidinones/synthèse chimique , Radiopharmaceutiques/synthèse chimique , Radio-isotopes du carbone/composition chimique , Marquage isotopiqueRÉSUMÉ
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.
Sujet(s)
Carboxypeptidases/antagonistes et inhibiteurs , Cyclohexanes/composition chimique , Cyclohexanes/pharmacologie , Antienzymes/composition chimique , Antienzymes/pharmacologie , Animaux , Cyclohexanes/pharmacocinétique , Découverte de médicament , Mâle , Souris , Souris de lignée C57BL , Structure moléculaire , Obésité/traitement médicamenteux , Relation structure-activitéRÉSUMÉ
We report the design and synthesis of a series of novel DGAT1 inhibitors in the benzimidazole class with a pyridyl-oxy-cyclohexanecarboxylic acid moiety. In particular, compound 11A is a potent DGAT1 inhibitor with excellent selectivity against ACAT1. Compound 11A significantly reduces triglyceride excursion in lipid tolerance tests (LTT) in both mice and dogs at low plasma exposure. An in vivo study in mice with des-fluoro analogue 10A indicates that this series of compounds appears to distribute in intestine preferentially over plasma. The propensity to target intestine over plasma could be advantageous in reducing potential side effects since lower circulating levels of drug are required for efficacy. However, in the preclinical species, compound 11A undergoes cis/trans epimerization in vivo, which could complicate further development due to the presence of an active metabolite.
RÉSUMÉ
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.