BACKGROUND:Forty million adults in the US suffer from anxiety disorders, making these the most common forms of mental illness. Transient receptor potential channel canonical subfamily (TRPC) members 4 and 5 are non-selective cation channels highly expressed in regions of the cortex and amygdala, areas thought to be important in regulating anxiety. Previous work with null mice suggests that inhibition of TRPC4 and TRPC5 may have anxiolytic effects.HC-070 IN VITRO:To assess the potential of TRPC4/5 inhibitors as an avenue for treatment, we invented a highly potent, small molecule antagonist of TRPC4 and TRPC5 which we call HC-070. HC-070 inhibits recombinant TRPC4 and TRPC5 homomultimers in heterologous expression systems with nanomolar potency. It also inhibits TRPC1/5 and TRPC1/4 heteromultimers with similar potency and reduces responses evoked by cholecystokinin tetrapeptide (CCK-4) in the amygdala. The compound is >400-fold selective over a wide range of molecular targets including ion channels, receptors, and kinases.HC-070 IN VIVO:Upon oral dosing in mice, HC-070 achieves exposure levels in the brain and plasma deemed sufficient to test behavioral activity. Treatment with HC-070 attenuates the anxiogenic effect of CCK-4 in the elevated plus maze (EPM). The compound recapitulates the phenotype observed in both null TRPC4 and TRPC5 mice in a standard EPM. Anxiolytic and anti-depressant effects of HC-070 are also observed in pharmacological in vivo tests including marble burying, tail suspension and forced swim. Furthermore, HC-070 ameliorates the increased fear memory induced by chronic social stress. A careful evaluation of the pharmacokinetic-pharmacodynamic relationship reveals that substantial efficacy is observed at unbound brain levels similar to, or even lower than, the 50% inhibitory concentration (IC50) recorded in vitro, increasing confidence that the observed effects are indeed mediated by TRPC4 and/or TRPC5 inhibition. Together, this experimental data set introduces a novel, high quality, small molecule antagonist of TRPC4 and TRPC5 containing channels and supports the targeting of TRPC4 and TRPC5 channels as a new mechanism of action for the treatment of psychiatric symptoms.

For the first time, we disclose the medicinal chemistry efforts at Neurogen Corporation that led to the discovery of the clinical phase I compound NGD-4715 (7), a selective, brain penetrant, orally bioavailable melanin-concentrating hormone receptor 1 antagonist. We discuss the optimization of an arylpiperazine serendipitous hit in a high-throughput screening that led to the discovery of NDT 9522320 (10), a useful tool compound that enabled target validation in rat and dog feeding models. Subsequent medicinal chemistry design led to the bicyclic core of NGD-4715. We recount how we arrived at selecting NGD-4715 as a development candidate and summarize our clinical experience with it. A number of syntheses are presented, which were explored as a prelude to the highly optimized chemical process synthesis used to support the IND-enabling toxicology program and deliver clinical supplies for the phase I studies. We discuss the backup strategy that led to NGD-0589, as well as the discovery of further improved compounds.

The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a nonselective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. The design and synthesis of a series of novel TRPV1 antagonists with a variety of different 6,6-heterocyclic cores is described, and an extensive evaluation of the pharmacological and pharmacokinetic properties of a number of these compounds is reported. For example, the 1,8-naphthyridine 52 was characterized as an orally bioavailable and brain penetrant TRPV1 antagonist. In vivo, 52 fully reversed carrageenan-induced thermal hyperalgesia (CITH) in rats and dose-dependently potently reduced complete Freund's adjuvant (CFA) induced chronic inflammatory pain after oral administration.

The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a non-selective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. During pre-clinical development, the 1,8-naphthyridine 2 demonstrated unacceptably high levels of irreversible covalent binding. Replacement of the 1,8-naphthyridine core by a pyrido[2,3-b]pyrazine led to the discovery of compound 26 which was shown to have significantly lower potential for the formation of reactive metabolites. Compound 26 was characterized as an orally bioavailable TRPV1 antagonist with moderate brain penetration. In vivo, 26 significantly attenuated carrageenan-induced thermal hyperalgesia (CITH) and dose-dependently reduced complete Freund’s adjuvant (CFA)-induced chronic inflammatory pain after oral administration.

Purpose: We examined the potential for the pro-inflammatory complement proteins C5a and C3a to increase VEGF expression in ARPE-19 cells. Materials and Methods: Expression of complement receptors in ARPE-19 cells was evaluated by RT-PCR. VEGF secretion from ARPE-19 cells treated with C5a or C3a was determined by ELISA. Results: C5a and C3a receptor, but not C5L2, were detected in human eye tissue and ARPE-19 cells. C5a, but not C3a, treatment increased VEGF secretion from ARPE-19 cells, an effect inhibited by the C5aR antagonist, NDT 9513727. Conclusions: C5a receptor mediates increased VEGF secretion from ARPE-19 cells, suggesting a role for the C5a receptor in the pathogenesis of macular degeneration.

A series of 5,6-diaryl-2-amino-pyrazines with potent CB1 antagonist-like activity were discovered and shown to have robust effects on food intake in vivo.

Beta-aryl-beta-ketophosphonates can be efficiently prepared in good yield by using a TFAA/85% H 3PO 4-mediated acylation of electron-rich arenes with phosphonoacetic acids. The conditions offer advantages over existing methods of preparing these useful compounds by not requiring the use of strong base, cryogenics, or an anhydrous and inert atmosphere. Furthermore, some functional groups not tolerated with the reaction conditions used in existing methods are compatible with the herein described conditions.

The design, synthesis, and structure-activity studies of a novel series of BK B(1) receptor antagonists based on a 1-benzylbenzimidazole chemotype are described. A number of compounds, for example, 38g, with excellent affinity for the cynomolgus macaque and rat bradykinin B(1) receptor were discovered.

There have been relatively few new mechanism-based approvals for nervous system relevant drugs over the past 5 years, despite the increasing budgets of pharmaceutical and biotechnology companies. The genomic revolution has provided scientists with many molecular targets for drug discovery and research advances in chemistry, drug metabolism, pharmacology, and toxicology have provided much insight into understanding the pitfalls of the drug discovery and development process. Herein is provided a perspective on both the opportunities and challenges in the discovery and development of novel medicines for the treatment of human CNS disorders.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A focused SAR exploration of the lead 4-aminoquinazoline TRPV1 antagonist 2 led to the discovery of compound 18. In rats, compound 18 is readily absorbed following oral dosing and demonstrates excellent in vivo potency and efficacy in an acute inflammatory pain model.

A scaleable route to 6-chloro-4-[2-(3-fluoropyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidine (NDT 9533750), a key intermediate to a series of novel subtype preferring GABAA partial agonists, is described in which various scaleup issues were addressed to provide an efficient and robust route for the preparation of kilogram quantities of the compound.