Christophe Genicot

First dual NK1 antagonists–serotonin reuptake inhibitors: synthesis and SAR of a new class of potential antidepressants

Compounds combining NK(1) antagonism and serotonin reuptake inhibition are described, and potentially represent a new generation of antidepressants. Compound 24 displays good affinities for both the NK(1) receptor and the serotonin reuptake site (32 and 25 nM, respectively).

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.

Dual NK1 antagonists: Serotonin reuptake inhibitors as potential antidepressants. Part 2: Sar and activity of benzyloxyphenethyl piperazine derivatives

The synthesis, structure-affinity relationship and activity of benzyloxyphenethyl piperazine derivatives combining NK(1) antagonism and serotonin reuptake inhibition is described. Compound 7u was shown to be active in animal models of 5-HT reuptake inhibition and central NK(1) receptor blockade, and was demonstrated to be orally active in an integrated model sensitive to both mechanisms. This class of compounds potentially represents a new generation of antidepressants.

Discovery of orally bioavailable NK1 receptor antagonists

Benzyloxyphenethylpiperazines are a new class of high affinity NK1 receptor antagonists. Oral bioavailability and selectivity can be fine tuned by the nature of the substituents on the basic nitrogen atom. Addition of substituents with a carboxylic acid group led to very selective and orally active NK1 antagonists free of interaction with L-type calcium channels.

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]

C−H Cyanation of 6-Ring N-Containing Heteroaromatics

Abstract Heteroaromatic nitriles are important compounds in drug discovery, both for their prevalence in the clinic and due to the diverse range of transformations they can undergo. As such, efficient and reliable methods to access them have the potential for far‐reaching impact across synthetic chemistry and the biomedical sciences. Herein, we report an approach to heteroaromatic C−H cyanation through triflic anhydride activation, nucleophilic addition of cyanide, followed by elimination of trifluoromethanesulfinate to regenerate the cyanated heteroaromatic ring. This one‐pot protocol is simple to perform, is applicable to a broad range of decorated 6‐ring N‐containing heterocycles, and has been shown to be suitable for late‐stage functionalization of complex drug‐like architectures.

Development of a Flow Photochemical Aerobic Oxidation of Benzylic C–H Bonds

A continuous mesofluidic process has been developed for benzylic C-H oxidation with moderate to good yields using a photocatalyst (riboflavin tetraacetate, RFT) activated by a UV lamp and an iron additive [Fe(ClO4)2] via incorporation of singlet oxygen (1O2) for the direct formation of oxidized C═O or CH-OH compounds.

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.