Allosteric modulation of AMPA, NR2B, mGlu2, mGlu5 and M1, targeting glutamatergic dysfunction, represents a significant area of research for the treatment of schizophrenia. Of these targets, clinical promise has been demonstrated using muscarinic activators for the treatment of Alzheimer’s disease (AD) and schizophrenia. These diseases have inspired researchers to determine the effects of modulating cholinergic transmission in the forebrain, which is primarily regulated by one of five subtypes of muscarinic acetylcholine receptor (mAChR), a subfamily of G-protein-coupled receptors (GPCRs). Of these five subtypes, M1 is highly expressed in brain regions responsible for learning, cognition and memory. Xanomeline, an orthosteric muscarinic agonist with modest selectivity, was one of the first compounds that displayed improvements in behavioral disturbances in AD patients and efficacy in schizophrenics. Since these initial clinical results, many scientists, including those in our laboratories, have strived to elucidate the role of M1 with compounds that display improved selectivity for this receptor by targeting allosteric modes of receptor activation. A survey of selected compounds in this area will be presented.

Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme responsible for the methylation of nicotinamide (NAM) using cofactor S-adenosylmethionine (SAM). NNMT overexpression has been linked to diabetes, obesity, and a variety of cancers. Successful development of potent and selective NNMT inhibitors could further reveal the role of NNMT in various diseases, potentially enabling new treatments for metabolic disorders and several cancers. In this work, structure-based rational design led to the development of potent and selective alkynyl bisubstrate inhibitors of NNMT. The reported nicotinamide-SAM conjugate (named NS1) features an alkyne as a key design element that closely mimics the linear, 180°transition state geometry found in the NNMT-catalyzed SAM → NAM methyl transfer reaction. NS1 was synthesized as a single enantiomer and diastereomer in 14 steps and found to be a high-affinity, subnanomolar NNMTinhibitor. An X-ray co-crystal structure and structure-activity relationship (SAR) study revealed the unique ability of an alkynyl linker to span the methyl transfer tunnel of NNMT with ideal shape complementarity.

The first total synthesis of Aplidiopsamine A, a rare 3H-pyrrolo[2,3-c]quinolone alkaloid from the Aplidiopsis confluata, has been achieved following the proposed biosynthesis. This biomimetic synthesis requires only 5 steps and proceeds in 20.8% overall yield. Biological evaluation across large panels of discrete molecular targets identified that Aplidiopsamine A is a highly selective PDE4 inhibitor, a target for numerous CNS disorders.

Abstract2-Iodoxybenzoic acid (IBX) is a convenient reagent for the dehydrogenation of tetrahydro-β-carbolines to their aromatic forms under mild conditions. The utility of the method was demonstrated in a total synthesis of the marine indole alkaloid eudistomin U.The aromatic β-carboline moiety is found in numerous natural products and synthetic congeners.1 Compounds bearing this ring system display a diverse range of biological properties including antimalarial,2 antitumor,3 and anti-HIV activities.4 Others show potent binding affinities toward benzodiazepine receptors in the central nervous system, thereby acting as diazepam antagonists.5 In light of these pharmacological properties, mild synthetic methods for the construction of the β-carboline unit are desirable. One strategy for its preparation centers on the formal dehydrogenation of a suitable tetrahydro-β-carboline precursor. Transformations of this type have been previously conducted by heating the substrate with palladium on carbon6 or sulfur7 in refluxing cumene or xylenes over extended periods of time. Other oxidizing agents such SeO 2 8 and MnO 2 9 also require high temperatures and must often be used in excess. Organic-based reagents capable of effecting the dehydrogenation are limited to quinone-derived reagents such as chloranil10 and DDQ11 and yields are often unsatisfactory. Trichloroisocyanuric acid (TCCA) has recently been identified as an additional oxidant.12We were prompted to seek a mild set of conditions for the aromatization of tetrahydro-β-carbolines during our studies in alkaloid synthesis. Aiming to improve upon existing methodologies, we desired a process that would employ an inexpensive oxidant and proceed smoothly at ambient temperature. In this Letter, we describe a new method to achieve this transformation and demonstrate its utility in a total synthesis of the marine indole alkaloid eudistomin U.Drawn to examples by Nicolaou and co-workers of iodine(V)-mediated syntheses of pyridines from N-heterocyclic precursors,13 our attention turned to hypervalent iodine reagents such as the Dess-Martin periodinane and 2-iodoxybenzoic acid (IBX).14 A survey

Herein, we report the discovery of a novel potent, selective, CNS penetrant, and orally bioavailable mGlu 4 PAM, VU0652957 (VU2957, Valiglurax). VU2957 possessed attractive in vitro and in vivo pharmacological and DMPK properties across species. To advance toward the clinic, a spray-dried dispersion (SDD) formulation of VU2957 was developed to support IND-enabling toxicology studies. Based on its overall profile, VU2957 was evaluated as a preclinical development candidate for the treatment of Parkinson's disease.

This letter describes the chemical optimization of a new series of M positive allosteric modulators (PAMs) based on a novel benzomorpholine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 (7), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties).

This letter describes the continued chemical optimization of the VU0453595 series of M1 positive allosteric modulators (PAMs). By surveying alternative 5,6- and 6,6-heterobicylic cores for the 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one core of VU453595, we found new cores that engendered not only comparable or improved M1 PAM potency, but significantly improved CNS distribution (Kps 0.3 to 3.1). Moreover, this campaign provided fundamentally distinct M1 PAM chemotypes, greatly expanding the available structural diversity for this valuable CNS target, devoid of hydrogen-bond donors.

An enantioselective formal total synthesis of the cytotoxic macrolide (+)-aspergillide C has been accomplished from (S)-(−)-glyceraldehyde acetonide and the Danishefsky–Kitahara diene. Strategic transformations include a hetero Diels–Alder reaction, Ferrier-type addition, and palladium-catalyzed oxidative lactonization to set key stereocenters within the dihydropyran core, followed by fragment coupling via (E)-selective Julia–Kocienski olefination.