Orally Bioavailable Macrocyclic Peptide That Inhibits Binding of PCSK9 to the Low Density Lipoprotein Receptor.

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.

CRTH2 antagonist MK-7246: a synthetic evolution from discovery through development.

In this paper, we report the development of different synthetic routes to MK-7246 (1) designed by the Process Chemistry group. The syntheses were initially designed as an enabling tool for Medicinal Chemistry colleagues in order to rapidly explore structure-activity relationships (SAR) and to procure the first milligrams of diverse target molecules for in vitro evaluation. The initial aziridine opening/cyclodehydration strategy was also directly amenable to the first GMP deliveries of MK-7246 (1), streamlining the transition from milligram to kilogram-scale production needed to support early preclinical and clinical evaluation of this compound. Subsequently a more scalable and cost-effective manufacturing route to MK-7246 (1) was engineered. Highlights of the manufacturing route include an Ir-catalyzed intramolecular N-H insertion of sulfoxonium ylide 41 and conversion of ketone 32 to amine 31 in a single step with excellent enantioselectivity through a transaminase process. Reactions such as these illustrate the enabling impact and efficiency gains that innovative developments in chemo- and biocatalysis can have on the synthesis of pharmaceutically relevant target molecules.

A cascade approach to cyclic aminonitrones: reaction discovery, mechanism, and scope.

Treatment of omega-epoxynitriles with hydroxylamine affords cyclic aminonitrones in a single step and with high stereoselectivity. The scope of this novel transformation was explored in a series of examples. The aminonitrone products were shown to be useful substrates for further selective elaboration.

Recent advances in biomimetic natural product synthesis.

This review highlights some of the most elegant and instructive biomimetic syntheses of natural products over the last few years, providing an updated overview of this area of research.

Cascade reactions in total synthesis.

The design and implementation of cascade reactions is a challenging facet of organic chemistry, yet one that can impart striking novelty, elegance, and efficiency to synthetic strategies. The application of cascade reactions to natural products synthesis represents a particularly demanding task, but the results can be both stunning and instructive. This Review highlights selected examples of cascade reactions in total synthesis, with particular emphasis on recent applications therein. The examples discussed herein illustrate the power of these processes in the construction of complex molecules and underscore their future potential in chemical synthesis.

Synthesis of iso-epoxy-amphidinolide N and des-epoxy-caribenolide I structures. Initial forays.

Two strategies for the projected total synthesis of the phenomenally potent antitumour macrolides amphidinolide N (1) and caribenolide I (2) are described. The title compounds are introduced as challenging and unique targets for chemical synthesis, and their retrosynthetic analysis is presented. The synthesis of the four defined key building blocks (10, 39, 67 and 72), required for the construction of amphidinolide N (1), in their enantiomerically pure forms, is described, followed by the coupling of 10, 39 and 72 through hydrazone alkylation processes to generate the complete C6-C29 carbon framework of the target compound (1). Fusion of the remaining C1-C5 sector (72) onto the molecule by metathesis-based methods was unsuccessful, resulting in the adoption of a second-generation strategy which called for the employment of one of the array of palladium-catalysed cross-coupling reactions to generate the C5-C6 carbon-carbon bond. Vinyl bromide 125, representing the C6-C29 skeleton of caribenolide I (2), was prepared through the sequential alkylation of hydrazone 10 with bromide 116 and iodide 55, but failed to engage in the appropriate cross-coupling reaction with a variety of C1-C4 partners. Despite these setbacks, the information gleaned from these endeavours was to prove invaluable in laying the foundation for the eventual successful approach to the macrocyclic structures of amphidinolide N (1) and caribenolide I (2).

Synthesis of iso-epoxy-amphidinolide N and des-epoxy-caribenolide I structures. Revised strategy and final stages.

A general and highly convergent synthetic route to the macrocyclic core structures of the antitumour agents amphidinolide N (1) and caribenolide I (2) has been developed, and the total synthesis of iso-epoxy-amphidinolide N and des-epoxy-caribenolide I structures is described. Central to the revised strategy was the use of a Horner-Wadsworth-Emmons olefination between beta-ketophosphonate 51 and aldehyde 14 to construct the C1-C13 sector common to both 1 and 2. Stereoselective alkylation of hydrazone 11 with iodide 65 and then with bromide 56 allowed for the rapid assembly of the complete caribenolide I carbon skeleton. Key steps in the completion of the synthesis of des-epoxy-caribenolide I structure 78 included hydrolysis of a sensitive methyl ester using Me(3)SnOH, followed by regioselective macrolactonisation of the resulting diol seco-acid and global deprotection. Coupling of hydrazone 11, bromide 56 and iodide 64 was followed by an analogous sequence of late-stage manoeuvres to arrive at the fully deprotected des-epoxy-amphidinolide N framework, obtained as a mixture of hemiacetal and bicyclic acetal 84. Regio- and diastereo-selective epoxidation of the C6 methylene group in bicyclic acetal 84 provided access to iso-epoxy-amphidinolide N stereoisomer 89.

Palladium-catalyzed cross-coupling reactions in total synthesis.

In studying the evolution of organic chemistry and grasping its essence, one comes quickly to the conclusion that no other type of reaction plays as large a role in shaping this domain of science than carbon-carbon bond-forming reactions. The Grignard, Diels-Alder, and Wittig reactions are but three prominent examples of such processes, and are among those which have undeniably exercised decisive roles in the last century in the emergence of chemical synthesis as we know it today. In the last quarter of the 20th century, a new family of carbon-carbon bond-forming reactions based on transition-metal catalysts evolved as powerful tools in synthesis. Among them, the palladium-catalyzed cross-coupling reactions are the most prominent. In this Review, highlights of a number of selected syntheses are discussed. The examples chosen demonstrate the enormous power of these processes in the art of total synthesis and underscore their future potential in chemical synthesis.

Metathesis reactions in total synthesis.

With the exception of palladium-catalyzed cross-couplings, no other group of reactions has had such a profound impact on the formation of carbon-carbon bonds and the art of total synthesis in the last quarter of a century than the metathesis reactions of olefins, enynes, and alkynes. Herein, we highlight a number of selected examples of total syntheses in which such processes played a crucial role and which imparted to these endeavors certain elements of novelty, elegance, and efficiency. Judging from their short but impressive history, the influence of these reactions in chemical synthesis is destined to increase.

A multicomponent coupling strategy suitable for the synthesis of the triene component of the oxazolomycin antibiotics.

Concise and versatile routes suitable for the synthesis of three geometric isomers of an analogue of the left hand triene sub-unit of oxazolomycin are reported. A strategy based upon a key Heck reaction was unsuccessful, and this was traced to a combination of steric encumbrance and electronic deactivation of the alkene substrate. An alternative Stille coupling strategy, however, proved to be both versatile and high yielding, and is potentially applicable to the synthesis of analogues with variation both in the side-chain geometry and in the identity of the terminal aromatic or heteroaromatic residue.