Discovery of a brain-sparing GIRK1/4 inhibitor for pharmacological cardioversion of atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and a significant risk factor for ischemic stroke and heart failure. Marketed anti-arrhythmic drugs can restore sinus rhythm, but with limited efficacy and significant toxicities, including potential to induce ventricular arrhythmia. Atrial-selective ion channel drugs are expected to restore and maintain sinus rhythm without risk of ventricular arrhythmia. One such atrial-selective channel target is GIRK1/4 (G-protein regulated inwardly rectifying potassium channel 1/4). Here we describe 14b, a potent GIRK1/4 inhibitor developed to cardiovert AF to sinus rhythm while minimizing central nervous system exposure - an issue with preceding GIRK1/4 clinical candidates.

A Condensed, Scalable Synthesis of Racemic Koningic Acid.

The natural product koningic acid (KA) is a selective covalent inhibitor of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a critical node in the glycolysis pathway. While KA is available commercially, sources are limited and its cost becomes rapidly prohibitive beyond the milligram scale. Additionally, a practical and flexible synthetic route to KA and analogs remains to be developed. Here we detail a new route that is operationally safer, scalable and offers a five-step reduction in the previously reported longest linear sequence.

Discovery and optimization of 2-pyridinone aminal integrase strand transfer inhibitors for the treatment of HIV.

HIV integrase strand transfer inhibitors (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naïve patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles. Herein, we detail medicinal chemistry efforts on a novel class of 2-pyridinone aminal InSTIs, inpsired by MK-0536, which led to the discovery of important lead molecules for our program. Systematic optimization carried out at the amide and aminal positions on the periphery of the core provided the necessary balance of antiviral activity and physiochemical properties. These efforts led to a novel aminal lead compound with the desired virological profile and preclinical pharmacokinetic profile to support a once-daily human dose prediction.

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.

Asymmetric total synthesis of (+)-luciduline: toward a general approach to related Lycopodium alkaloids.

As part of a research program directed toward the synthesis of Lycopodium alkaloids, a multigram scale asymmetric synthesis of intermediate 11 was achieved in 11 steps from pyridine (17). In addition to our alkene metathesis strategy, a key feature of this synthetic approach consists of a Fukuyama's Diels-Alder cycloaddition between 1,2-dihydropyridine and acrolein using MacMillan's catalyst (18) on a 50 g scale. This led to a 12-step catalytic asymmetric synthesis of (+)-luciduline (1). A broader subset of Lycopodium alkaloids could also be obtained, as demonstrated by the derivatization of 11 into advanced intermediates for the synthesis of some of these natural products.

Intramolecular pyridine activation-dearomatization reaction: highly stereoselective synthesis of polysubstituted indolizidines and quinolizidines.

An unprecedented intramolecular pyridine activation-asymmetric dearomatization reaction is described. This process produces 5-substituted indolizidines and 6-substituted quinolizidines in excellent yields and in a highly regio- and diastereoselective fashion. Formal syntheses of trans-indolizidine alkaloids are presented along with some preliminary results in the formation of C-5 quaternary centers.

Silver ion-induced Grob fragmentation of gamma-amino iodides: highly stereoselective synthesis of polysubstituted piperidines.

A new concerted silver ion-mediated Grob fragmentation process is described in which a 1,2-dihydropyridinium ion is formed and trapped in situ with Grignard reagents in a highly regio- and diastereoselective fashion. Using this methodology, 2,3,6-trisubstituted piperidines were synthesized in good yields and further derivatized to polysubstituted indolizidine.

Total synthesis of (+)-lepadin B: stereoselective synthesis of nonracemic polysubstituted hydroquinolines using an RC-ROM process.

This communication describes a new tandem metathesis reaction for which an RC-ROM mechanism was experimentally supported. This process was successfully applied to the synthesis of cis-fused polyhydroquinolines enabling a short stereoselective total synthesis of ent-lepadin B.

Highly chemoselective metal-free reduction of tertiary amides.

This communication describes the chemoselective metal-free reduction of tertiary amides to the corresponding amines. Hantzsch ester is used as a mild reducing agent for the reduction of trifluoromethanesulfonic anhydride activated amides providing the tertiary amines with high functional group tolerance.

Competition between alkenes in intramolecular ketene-alkene [2 + 2] cycloaddition: what does it take to win?

In the course of developing a new synthetic methodology using ketenes in sequential cycloaddition steps, we were faced with a competition problem with molecules containing a ketene tethered to more than one reacting partner. To pinpoint the electronic and tethering requirements for a chemoselective reaction, we undertook a series of ketene-alkene [2 + 2] cycloaddition competition experiments. Those experiments were conducted on molecules containing either two identical alkenes having different tether lengths or two alkenes having the same tether length but being electronically different. We demonstrated that the reaction is much faster for forming five-membered rings than six-membered rings and calculated the Hammett constant rho for intramolecular ketene-alkene [2 + 2] cycloadditions to be -1.39.

Preparation of 1,5-methano-2,3,4,5- tetrahydro-1H-3-benzazepine via Pd-catalyzed cyclization.

[reaction: see text] A new approach to prepare 1,5-methano-2,3,4,5-tetrahydro-1H-3-benzanepine (1) is discussed. This strategy utilized a tandem Michael addition and Pd-catalyzed cyclization to afford cyanobenzofulvene acetal 13. This indene intermediate (13) was subjected to hydrogenolysis to provide an amino ester (12) and was cyclized with base to afford lactam 5. The lactam (5) was reduced with borane to afford the desired benzazepine (1).