Diastereoselective Reductive Etherification Via High-Throughput Experimentation: Access to Pharmaceutically Relevant Alkyl Ethers.

This manuscript describes the development of the first diastereoselective intermolecular synthesis of alkyl ethers via reductive etherification of diverse ketones or aldehydes with alcohols. Key to this development was the use of low-temperature high-throughput experimentation (HTE) technologies that enabled rapid reaction optimizations and parallel synthesis. A broad scope of pharmaceutically relevant substrates was surveyed, which formed alkyl ethers effectively. In addition, we demonstrated that the diastereoselectivity of this transformation can be readily modulated by prudent selection of the reductant.

Asymmetric Synthesis of Tertiary and Secondary Cyclopropyl Boronates via Cyclopropanation of Enantioenriched Alkenyl Boronic Esters.

The cyclopropanation of alkenyl boronates and subsequent derivatization of the boronate handle are a convenient strategy to quickly build molecular complexity and access diverse compounds with a high sp3 fraction. Herein, we describe the asymmetric cyclopropanation of enantioenriched hydrobenzoin-derived alkenyl boronic esters toward the synthesis of tertiary and secondary cyclopropyl boronates.

Development of ProTx-II Analogues as Highly Selective Peptide Blockers of Nav1.7 for the Treatment of Pain.

Inhibitor cystine knot peptides, derived from venom, have evolved to block ion channel function but are often toxic when dosed at pharmacologically relevant levels in vivo. The article describes the design of analogues of ProTx-II that safely display systemic in vivo blocking of Nav1.7, resulting in a latency of response to thermal stimuli in rodents. The new designs achieve a better in vivo profile by improving ion channel selectivity and limiting the ability of the peptides to cause mast cell degranulation. The design rationale, structural modeling, in vitro profiles, and rat tail flick outcomes are disclosed and discussed.

Structure-Activity Relationship of Novel and Selective Biaryl-Chroman GPR40 AgoPAMs.

A series of biaryl chromans exhibiting potent and selective agonism for the GPR40 receptor with positive allosteric modulation of endogenous ligands (AgoPAM) were discovered as potential therapeutics for the treatment of type II diabetes. Optimization of physicochemical properties through modification of the pendant aryl rings resulted in the identification of compound AP5, which possesses an improved metabolic profile while demonstrating sustained glucose lowering.

Design and Synthesis of Novel, Selective GPR40 AgoPAMs.

GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia. GPR40 agoPAMs have shown superior efficacy to partial agonists as assessed in a glucose tolerability test (GTT). Herein, we report the discovery and optimization of a series of potent, selective GPR40 agoPAMs. Compound 24 demonstrated sustained glucose lowering in a chronic study of Goto Kakizaki rats, showing no signs of tachyphylaxis for this mechanism.

A Synthesis of a Spirocyclic Macrocyclic Protease Inhibitor for the Treatment of Hepatitis C.

The development of a convergent and highly stereoselective synthesis of an HCV NS3/4a protease inhibitor possessing a unique spirocyclic and macrocyclic architecture is described. A late-stage spirocyclization strategy both enabled rapid structure-activity relationship studies in the drug discovery phase and simultaneously served as the basis for the large scale drug candidate preparation for clinical use. Also reported is the discovery of a novel InCl3-catalyzed carbonyl reduction with household aluminum foil or zinc powder as the terminal reductant.

Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.

We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.

Enantioselective Synthesis of α-Methyl-ß-cyclopropyldihydrocinnamates.

α- and ß-substitution of dihydrocinnamates has been shown to increase the biological activity of various drug candidates. Recently, we identified enantio- and diastereopure α-methyl-ß-cyclopropyldihydrocinnamates to be important pharmacophores in one of our drug discovery programs and endeavored to devise an asymmetric hydrogenation strategy to improve access to this valuable framework. We used high throughput experimentation to define stereoconvergent Suzuki-Miyaura cross-coupling conditions affording (Z)-α-methyl-ß-cyclopropylcinnamates and subsequent ruthenium-catalyzed asymmetric hydrogenation conditions affording the desired products in excellent enantio- and diastereoselectivities. These conditions were executed on multigram to kilogram scale to provide three key enantiopure α-methyl-ß-cyclopropyldihydrocinnamates with high selectivity.

Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors.

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.

Development of a novel class of potent and selective FIXa inhibitors.

Using structure based drug design (SBDD), a novel class of potent coagulation Factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds demonstrated oral bioavailability in rat IV/PO pharmacokinetic (PK) studies. Finally, the pharmacodynamics (PD) of this class of molecules was evaluated in Thrombin Generation Assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.

Synthesis of vaniprevir (MK-7009): lactamization to prepare a 20-membered [corrected] macrocycle.

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.

Synthesis of the C6-C21 segment of amphidinolide E.

[reaction: see text] A convergent approach to a C6-C21 segment of the polyketide amphidinolide E has been developed through combination of three subunits by allenylindium bromide-aldehyde addition and Suzuki sp2-sp3 coupling.