Below you can find descriptions of ongoing research projects:
Palladium-catalyzed coupling reactions
BACKGROUND: Palladium-catalyzed Cross-couplings, carbonylations and Heck reactions constitute important tools in medicinal chemistry since they allow preparation of compounds substituted with a variety of functional groups, with diverse physicochemical properties, from a common precursor. In the field of carbonylative transformations, the usefulness increases dramatically if CO-free methodologies might be further developed. Despite the extensive use of the Heck coupling, the reaction still suffers from severe limitations. These include unsatisfactory control of chemoselectivity, regioselectivity, stereoselectivity, double bond migration and selectivity in multifunctionalizations. Provided these factors could be controlled, the Heck reaction would have a considerably greater potential in selective organic synthesis and in medicinal chemistry, in particular.
METHOD: For development of new palladium-catalyzed carbonylative coupling reactions we investigate new double vial approaches using Mo(CO)6 as the CO-source. Unexplored nucleophiles are being systematically evaluated. In the Heck chemistry arena, we are focusing our research efforts on the generation of the starting organopalladium intermediate, insertion and double bond migration processes with the ultimate goal of developing robust and general synthetic methods. We investigate and expand the scope of chelation-controlled and ligand controlled Heck reactions. A profound mechanistic insight on metal-ligand interactions is a prerequisite for successful programs.
AIM: To develop new robust and selective metal-catalyzed coupling reactions of importance in medicinal- and pharmaceutical chemistry.
Continuous flow chemistry
BACKGROUND: Within the pharmaceutical and fine chemistry communities, the use of continuous flow synthesis has attracted considerable recent interest. Key advantages associated with continuous flow protocols, in comparison with traditional batch techniques, include the ability to independently control and to quickly evaluate reaction parameters such as temperature, residence time and reaction stoichiometry. Clearly, this allows for fast reaction optimization since it is possible to analyze the first drops of the processed product mixture or to use in-line detection. In addition, flow techniques provide unique possibilities for facile and straightforward scale-up (scale-out) in a standard research laboratory environment. Further, the heating and safety advantages of MW heating and flow processing, have prompted the development of combined MW-based, continuous-flow lab instrumentation, most of them being modified batch MW-synthesizers.
METHOD: The new MW-flow equipment developed by us utilizes an antenna and a semiconductor based MW generator, and provides an evenly distributed high density MW field along the length of the tube reactor. This feature is unique for this technology and highly suitable for flow applications, especially compared to commercially available magnetron instruments providing focused heating (cold- and hot spots) not suitable for flow conditions. In addition, the tube reactors are fabricated from both MW transparent and MW absorbing materials respectively, allowing the use of strictly non-polar solvents or extreme temperature conditions. An additional advantage with silicon carbide (SiC) tube reactors is the reduced risk for reactor failure due to superheating of precipitated metal. After five years of development we have now formed an experienced team around this technology, ready to explore the full potential of MW-flow in method development and for preparation of building blocks and key intermediates of importance for chemical biology and drug discovery.
AIM: To develop, evaluate and utilize new compact equipment for laboratory-scale flow synthesis.
Vesicular acetylcholine transporter inhibitors
BACKGROUND: Positron emission tomography (PET) is a non-invasive diagnostic imaging technique that use organic compounds labelled with short-lived positron emitting radionuclides for in vivo studies. For this purpose radiolabeled compound (tracers) are needed that specifically interacts with a receptor, transporter or enzyme protein enabling the determination of regional expression of the specific protein and also to be used as biomarkers for the measurements of drug effects, such a as receptor occupancy or enzyme inhibition. The further developments of the PET technology is very dependent on access to new tracers. The potential tracer candidates are labelled with 11C (half-life 20.4 min) or 18F (half-life 109 min).
The vesicular acetylcholine transporter (VAChT) is acknowledged as a marker for cholinergic neurons. The transporter is localized presynaptically in cholinergic nerve terminals where it transports newly synthesized acetylcholine into synaptic vesicles. In various neurodegenerative diseases, the most notable examples being Alzheimer’s disease (AD) and Parkinson’s disease (PD), the loss of cholinergic neurons is highly linked to disease progression as the reduction of cholinergic neurons in the cortex has been coupled to the loss of cognitive abilities. Early detection is important as the limited treatment arsenal is predicted to be most beneficial in the early stages of AD. A suitable PET tracer for VAChT would help enabling visualization and quantification of early AD.
METHOD: PET tracer candidates are designed and selected based on requirements for specificity and ease of radiolabeling. The use of palladium-promoted 11CO-carbonylations allows the preparation of libraries of labelled compounds from a common precursor, which enables fast and efficient screening of potential VAChT PET tracers candidates with variations in molecular properties. Employing this researchmethodology, promising tracers candidates can, after in vitro studies, directly proceed to ex vivo- and preclinical PET studies.
AIM: To develop and identify new VAChT tracers with improved properties for early AD diagnosis.
Angiotensin II AT2 receptor antagonists
MEDICAL NEED: There is an unmet medical need for efficient treatment of neuropathic pain. Current therapy needs to be improved due to dose-limiting side effects and the lack of response in many patients. It is estimated that only one in four patients with neuropathic pain experiences over 50% pain relief. Neuropathic pain is defined as pain arising as direct consequence of a lesion or disease affecting the somatosensory system. The causes of neuropathic pain are diverse and include a) diabetes (diabetic neuropathy), b) viruses (e.g. post herpetic neuralgia; PHN) c) cancer or its treatment with therapy agents (e.g. chemotherapy induced neuropathy), and d) nerve trauma (peripheral nerve injury induced neuropathy).
PROJECT RATIONAL: Angiotensin II induces neuronal excitability through stimulation of the angiotensin II, type 2 receptor (AT2R). Hyperexcitability of dorsal root ganglion neurons is a key mechanism that contributes to neuropathic pain. The new AT2R antagonists, anticipated to act via peripheral mechanisms is expected to be devoid of the severe CNS related adverse effects encountered with current pharmacotherapy, e.g. with the GABA analogue pregabalin.
AIM: To design, synthesize and develop selective, potent and bioavailable peptidomimetic AT2R antagonists for the treatment of neuropathic pain, (primarily diabetic neuropathy, post herpetic pain and common neuropathic pain from herniated disc) and to take advantage of our experience from drug discovery programs in the AT2R area. To validate the AT2R as a new target for analgesics.
Angiotensin IV mimetics
MEDICAL NEED: It is estimated that as high as 20-25% of the populations over 80 years of age suffer from cognitive impairment or age-related cognitive decline. Alzheimer’s disease (AD) accounts for 60-70% of the cases of dementia. There are more than 100 000 people in Sweden with Alzheimer’s disease. Consequently, there is a strong demand for efficient new chemical entities for the treatment of the cognitive decline associated with AD, brain trauma, and cerebral ischemia since the data from the clinical evaluations of the drugs used today have been mostly disappointing. In addition, the rate of failure in clinic of new drug candidates is also high and therefore new avenues, relying on new and alternative mechanisms of action have to be explored constantly.
PROJECT RATIONAL: It is reported that intracerebroventricular (icv) injection of the hexapeptide angiotensin IV (Ang IV), a degradation fragment of angiotensin II, improves memory and learning in rat and mice as deduced from several studies in a large variety of animal models. High densities of binding sites for Ang IV were found in areas of the brain associated with cognitive, sensory and motor functions, including the hippocampus. The Ang IV receptor was identified as insulin-regulated aminopeptidase (IRAP), a single-spanning transmembrane zinc-metallopeptidase that belongs to the M1 family of aminopeptidases. Ang IV acts as an inhibitor of IRAP (Ki = 56 nM).
AIM: To develop potent unique peptidomimetics that enter the brain after oral administration and that inhibit insulin-regulated aminopeptidase (IRAP) as a new class of cognitive enhancers for use in the therapy of Alzheimer’s disease.