Eric Jnoff

Binding Mode and Structure-Activity Relationships around Direct Inhibitors of the Nrf2-Keap1 Complex.

An X‐ray crystal structure of Kelch‐like ECH‐associated protein (Keap1) co‐crystallised with (1S,2R)‐2‐[(1S)‐1‐[(1,3‐dioxo‐2,3‐dihydro‐1H‐isoindol‐2‐yl)methyl]‐1,2,3,4‐tetrahydroisoquinolin‐2‐carbonyl]cyclohexane‐1‐carboxylic acid (compound (S,R,S)‐1 a) was obtained. This X‐ray crystal structure provides breakthrough experimental evidence for the true binding mode of the hit compound (S,R,S)‐1 a, as the ligand orientation was found to differ from that of the initial docking model, which was available at the start of the project. Crystallographic elucidation of this binding mode helped to focus and drive the drug design process more effectively and efficiently.

Reversible inhibition of the glycine transporter GlyT2 circumvents acute toxicity while preserving efficacy in the treatment of pain.

Available medications for chronic pain provide only partial relief and often cause unacceptable side effects. There is therefore a need for novel molecular targets to develop new therapeutics with improved efficacy and tolerability. Despite encouraging efficacy data in rodents with inhibitors of the neuronal glycine transporter‐2 (GlyT2), there are also some reports of toxicity and their development was discontinued.

Discovery of Heterocyclic Nonacetamide Synaptic Vesicle Protein 2A (SV2A) Ligands with Single-Digit Nanomolar Potency: Opening Avenues towards the First SV2A Positron Emission Tomography (PET) Ligands

The role of the synaptic vesicle protein 2A (SV2A) protein, target of the antiepileptic drug levetiracetam, is still mostly unknown. Considering its potential to provide in vivo functional insights into the role of SV2A in epileptic patients, the development of an SV2A positron emission tomography (PET) tracer has been undertaken. Using a 3D pharmacophore model based on close analogues of levetiracetam, we report the rationale design of three heterocyclic non‐acetamide lead compounds, UCB‐A, UCB‐H and UCB‐J, the first single‐digit nanomolar SV2A ligands with suitable properties for development as PET tracers.

Discovery of selective alpha(2C) adrenergic receptor agonists.

Neuropathic pain has recently been defined by the International Association for the Study of Pain (IASP) as “pain caused by a lesion or disease of the somatosensory system”. Neuropathic pain is chronic and may involve the central nervous system (CNS) (e. g. , stroke-related pain), as well as the peripheral nervous system (e. g. , trauma, resection, infection or progressive degeneration of a peripheral nerve). Examples of neuropathic pain include diabetic painful neuropathy, post-herpetic neuralgia, trigeminal neuralgia, cancerand HIV-related neuropathic pain, and iatrogenic neuropathic pain, associated with postsurgical neuropathy and neuropathies induced by cancer chemotherapy or antiretroviral drugs. Currently marketed drugs treating neuropathic pain are not optimal since they alleviate pain in only about 50 % of patients, making the treatment of neuropathic pain an unmet medical need. 4] Anti-epileptic drugs, such as gabapentin (Neurontin) and pregabalin (Lyrica), are the most commonly prescribed treatment. Delineating the specific role of different neurotransmitter–receptor systems in conducting pain messages has been the subject of intense research efforts. In particular, monoaminergic neurotransmitters, including serotonin, dopamine and noradrenaline (NA), are considered as mechanistic targets for pain. For instance, Tanabe and co-workers have provided evidence that gabapentin is characterized by a supraspinal site of action, in which central NA is involved. Their results indicate that gabapentin acts on supraspinal structures to activate the descending noradrenergic system. This terminates in the lumbar spinal cord, where NA interacts with a2 adrenergic receptors (ARs) to reduce the transmission of nociceptive information. The role of the noradrenergic system in pain mechanisms was confirmed when the drug clonidine (1), an a2-AR agonist and initially designed to reduce blood pressure in patients with essential hypertension, demonstrated marked anesthetic and analgesic properties. Clonidine became the first drug to be approved by the US Food and Drug Administration (FDA) for the treatment of cancer-related neuropathic pain as a substitute for opioids in patients suffering from excessive tolerance-related side effects. However, clonidine produces clinically relevant, dose-limiting adverse effects, such as arterial hypotension and sedation, that negatively impact its use, which, in cancer neuropathy, is limited to spinal infusion. The neurotransmitter NA acts through several ARs, including a2-ARs belonging to the seven-transmembrane G protein-coupled receptors (GPCRs). The a2-ARs are subdivided into a2A/D, a2B and a2C subtypes, [9–11] where a2A/D-AR is a global nomenclature for the human a2Aand murine a2D-AR orthologues. [12]

Advantageous safety profile of a dual selective alpha2C agonist/alpha2A antagonist antinociceptive agent

A selective α2C‐adrenoceptor (AR) agonist was developed for the treatment of neuropathic pain. The objective was to dissociate analgesic activity from cardiovascular and sedative side effects commonly observed with nonselective agents. A 2‐amino‐oxazoline derivative (compound A), identified as a dual α2C‐AR agonist/α2A‐AR antagonist in in vitro‐binding assays, exhibited in vivo efficacy in rodent pain models. Its safety profile was compared with that of clonidine in six different in vivo models. Contrary to clonidine, compound A did not induce hypotension in pentobarbital‐anesthetized rats, in conscious spontaneous hypertensive rats, or in telemetered dogs. Both agents induced similar dose‐dependent decreases in heart rate in dogs and rats. In anesthetized pithed rats, clonidine showed dose‐dependent hypertension and inhibited electrical nerve stimulation‐induced tachycardia at doses close to its efficacious doses in the mouse formalin test, while compound A had much weaker vasoconstrictive and antichronotropic effects. Finally, in a mouse Irwin test, no sedation was observed with compound A at 30‐fold its ED50 in the mouse formalin test, while sedative effects of clonidine started from three‐fold its ED50. These data confirm the advantageous safety profile of the new dual α2C‐AR agonist/α2A‐AR antagonist agent vs. the nonselective agonist clonidine.

Discovery of a small molecule modulator of the Kv1.1/Kvβ1 channel complex that reduces neuronal excitability and in vitro epileptiform activity

Kv1.1 (KCNA1) channels contribute to the control of neuronal excitability and have been associated with epilepsy. Kv1.1 channels can associate with the cytoplasmic Kvβ1 subunit resulting in rapid inactivating A‐type currents. We hypothesized that removal of channel inactivation, by modulating Kv1.1/Kvβ1 interaction with a small molecule, would lead to decreased neuronal excitability and anticonvulsant activity.

Back-up strategies in drug discovery: what, how and when?

The management of back-up strategies in drug discovery and development is usually done on an ad hoc basis depending upon a series of external factors including overall portfolio status and resource and/or budget availability. These are however an essential component of risk management and merit a more structured and systematic conduct throughout the lifetime of a project. An approach based upon a thorough alignment of decision points and data availability as well as a tailor-made progression of various types of back-up program as a function of project categorization is suggested.