Identification of potent, highly constrained CGRP receptor antagonists.

A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint was identified. The combination of the quinoline constraint with a tricyclic benzimidazolinone left hand fragment produced an analog with picomolar potency (14, CGRP K(i)=23 pM). Further optimization of the tricycle produced a CGRP receptor antagonist that exhibited subnanomolar potency (19, CGRP K(i)=0.52 nM) and displayed a good pharmacokinetic profile in three preclinical species.

Stereoselective formation of a functionalized dipeptide isostere by zinc carbenoid-mediated chain extension.

The application of a zinc carbenoid-mediated chain-extension reaction to a functionalized peptide isostere is reported. The cleavage site of human CVM protease was utilized as a target for testing the synthetic methodology. The utility of this chain-extension reaction is demonstrated in the preparation of an amino acid-derived alpha-unsubstituted gamma-keto ester, which is incorporated into a framework that mimics a tetrapeptide. The identification of a suitable protecting group strategy facilitated the application of a tandem reaction for the incorporation of an alpha-side chain, and the use of an oxazolidinone auxiliary provided excellent diastereocontrol in a tandem chain-extension-aldol reaction. Stereoselectivity of the tandem chain-extension-aldol reaction was determined through application of a CAN-mediated oxidative cleavage reaction.

The discovery of highly potent CGRP receptor antagonists.

Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25, CGRP K(i)=40pM). The closely related compound 27 demonstrated good oral bioavailability in dog and rhesus.

The identification of potent, orally bioavailable tricyclic CGRP receptor antagonists.

A series of tricyclic CGRP receptor antagonists was optimized in order to improve oral bioavailability. Attenuation of polar surface area and incorporation of a weakly basic indoline nitrogen led to compound 5, a potent antagonist with good oral bioavailability in three species.

Gut Microbiome: Profound Implications for Diet and Disease.

The gut microbiome plays an important role in human health and influences the development of chronic diseases ranging from metabolic disease to gastrointestinal disorders and colorectal cancer. Of increasing prevalence in Western societies, these conditions carry a high burden of care. Dietary patterns and environmental factors have a profound effect on shaping gut microbiota in real time. Diverse populations of intestinal bacteria mediate their beneficial effects through the fermentation of dietary fiber to produce short-chain fatty acids, endogenous signals with important roles in lipid homeostasis and reducing inflammation. Recent progress shows that an individual's starting microbial profile is a key determinant in predicting their response to intervention with live probiotics. The gut microbiota is complex and challenging to characterize. Enterotypes have been proposed using metrics such as alpha species diversity, the ratio of Firmicutes to Bacteroidetes phyla, and the relative abundance of beneficial genera (e.g., Bifidobacterium, Akkermansia) versus facultative anaerobes (E. coli), pro-inflammatory Ruminococcus, or nonbacterial microbes. Microbiota composition and relative populations of bacterial species are linked to physiologic health along different axes. We review the role of diet quality, carbohydrate intake, fermentable FODMAPs, and prebiotic fiber in maintaining healthy gut flora. The implications are discussed for various conditions including obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, depression, and cardiovascular disease.

Potent benzimidazolone-based CGRP receptor antagonists.

The previously disclosed spirohydantoin-based CGRP receptor antagonists were optimized for potency through modification of the benzimidazolone substituents. Compounds were identified which had minimal shift in the cAMP functional assay containing 50% human serum. Blockade of CGRP-mediated vasodilation was observed with these compounds in a rhesus pharmacodynamic assay and the in vivo potency correlated with the in vitro activity in the serum-shifted functional assay.

Progress towards validating the NMDA receptor hypofunction hypothesis of schizophrenia.

This article describes recent progress towards validation of the N-methyl-D-aspartate (NMDA) receptor hypofunction hypothesis of schizophrenia in preclinical models. Schizophrenia, a complex disease characterized by positive, negative and cognitive symptoms, affects 1% of the world population and requires lifelong, daily maintenance therapy. For the last several decades, thinking in this field has been dominated by the hypothesis that hyperfunction of dopamine pathways played a key role in schizophrenia. However, the therapeutic agents developed from this hypothesis have a slow onset of action and tend to improve only the positive symptoms of the disease. The NMDA receptor antagonist PCP has been shown to induce the positive, negative and cognitive symptoms of schizophrenia in healthy patients and cause a resurgence of symptoms in stable patients. These observations led to the NMDA receptor hypofunction hypothesis as an alternative theory for the underlying cause of schizophrenia. According to this hypothesis, any agent that can potentiate NMDA receptor currents has the potential to ameliorate the symptoms of schizophrenia. To date, NMDA receptor currents can be modulated by either direct action on modulatory sites on the NMDA receptor (i.e., the glycine co-agonist binding site) or indirectly by activation of G-protein coupled receptors (GPCRs) known to potentiate NMDA receptor function (i.e., mGluR5). This review will discuss the NMDA receptor hypofunction hypothesis, the NMDA receptor as an emerging target for the development of novel antipsychotic agents and progress towards in vivo target validation with GlyT1 inhibitors and mGluR5 positive allosteric modulators. Other potential targets for modulating NMDA receptor currents (polyamine sites, muscarinic receptors, etc...) will also be addressed briefly.

Discovery and Optimization of a Series of Pyrimidine-Based Phosphodiesterase 10A (PDE10A) Inhibitors through Fragment Screening, Structure-Based Design, and Parallel Synthesis.

Screening of a fragment library for PDE10A inhibitors identified a low molecular weight pyrimidine hit with PDE10A Ki of 8700 nM and LE of 0.59. Initial optimization by catalog followed by iterative parallel synthesis guided by X-ray cocrystal structures resulted in rapid potency improvements with minimal loss of ligand efficiency. Compound 15 h, with PDE10A Ki of 8.2 pM, LE of 0.49, and >5000-fold selectivity over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity after ip dosing.

NR2B-selective N-methyl-D-aspartate antagonists: synthesis and evaluation of 5-substituted benzimidazoles.

Two classes of 5-substituted benzimidazoles were identified as potent antagonists of the NR2B subtype of the N-methyl-d-aspartate (NMDA) receptor. Selected compounds show very good selectivity versus the NR2A, NR2C, and NR2D subtypes of the NMDA receptor as well as versus hERG-channel activity and alpha(1)-adrenergic binding. Benzimidazole 37a shows excellent activity in the carrageenan-induced mechanical hyperalgesia assay in rats as well as good pharmacokinetic behavior in dogs.

Studies on the Diastereoselective Preparation of Bis-cyclopropanes.

The identification of two natural products, FR-900848 and U-106305, has stimulated interest concerning the relationship between configurational isomerism, conformational isomerism, and biological activity of polycyclopropanes. Efforts to investigate the relationship between configurational and conformational isomerism through molecular modeling suggest that significantly different three-dimensional structures will result from unique primary structures. Any effort to address these issues demands that stereoselective methods for the preparation of polycyclopropanes be developed. We have investigated the application of zinc-carbenoid cyclopropanation in the presence of chiral dioxaboralanes to the preparation of eight stereochemically unique bicyclopropanes. The trans-vinylcyclopropane starting materials demonstrated very little substrate-induced stereoselectivity, while the cis-vinylcyclopropane demonstrates modest to excellent stereocontrol. A model for the substrate-based stereocontrol is proposed. We also used the spectroscopic data gathered in this investigation to probe the substrate-mediated stereocontrol in the rhodium(II)-catalyzed cyclopropanation of vinylcyclopropanes with ethyl diazoacetate.

Inhibition of glycine transporter 1 attenuates nicotine- but not food-induced cue-potentiated reinstatement for a response previously paired with sucrose.

RATIONALE: Compounds which decrease NMDA receptor functioning, such as PCP and ketamine have abuse liability, whereas co-agonists of the NMDA receptor attenuate some of the behavioral and neurochemical effects of stimulant drugs. Here we examined the effects of a glycine transporter (GlyT1) inhibitor, which elevates glycine and hence NMDA signaling, on the behavioral effects of nicotine. OBJECTIVES: To examine the influence of a novel potent, selective, and brain penetrant GlyT1 inhibitor, compound 5 {(2-chloro-N-[1-(ethylsulfonyl)-4-isobutylpiperidin-4-yl]methyl)}-4-(trifluoromethyl)benzamide; human IC(50)=22 nM; rat=30 nM), on nicotine-induced potentiation of progressive ratio responding for a food reward and nicotine- and food-induced cue-potentiated reinstatement for a response previously paired with sucrose. RESULTS: Compound 5 (33 mg/kg; p.o.; achieving approximately 62% GlyT1 blockade) significantly attenuated nicotine-, but not food-induced cue-potentiated reinstatement for a response previously paired with sucrose whereas a lower dose (11 mg/kg, which achieved approximately 34% GlyT1 blockade) did not. The effect of the higher dose was similar to that observed for mecamylamine (1mg/kg i.p.), a non-selective nicotinic receptor antagonist. CONCLUSIONS: These results suggest that compound 5 influences the ability of nicotine to promote reinstatement in the presence of a cue embedded with incentive motivation. Given the hypothesized contribution of reinstatement and conditioned stimuli to drug abuse and relapse, these findings suggest that GlyT1 inhibitors could have utility for treating nicotine addiction.

Identification of novel, orally bioavailable spirohydantoin CGRP receptor antagonists.

A rapid analogue approach to identification of spirohydantoin-based CGRP antagonists provided novel, low molecular weight leads. Modification of these leads afforded a series of nanomolar benzimidazolinone-based CGRP receptor antagonists. The oral bioavailability of these antagonists was inversely correlated with polar surface area, suggesting that membrane permeability was a key limitation to absorption. Optimization provided compound 12, a potent CGRP receptor antagonist (K(i)=21nM) with good oral bioavailability in three species.