An improved L-DOPA-like compound for treatment of Parkinson's Disease and related movement disorders
Development status: Preclinical
Description: L-DOPA in fixed combinations with a peripherally active DOPA decarboxylase inhibitors (DDI) to date is the gold standard in the treatment of Parkinsonīs Disease (PD). The rationale for this treatment is to locally limit the generation of Dopamine (DA) by decarboxylation of L-DOPA to the brain. The L-DOPA/DDI treatment usually provides a sustained clinical benefit and up to now is the only PD treatment, which proved to prolong life expectancy of PD patients. However, L-DOPA exhibits a wide range of inter- and intra-patient variations in the rate and extent of absorption. Furthermore, disabling motor effects such as dyskinesia and motor fluctuations and certain toxic effects develop at chronic L-DOPA therapy and limit its long-term use. Structual fluctuations of dopamin seem to be closely related to dyskinesias, and "on-off"-phenomene, especially in late stage PD patients at high L-Dopa doses. When systemic modification of the L-Dopa, and dopamine metabolism were introduced, BDD-206XX at the first time modified PK of striatal dopamine directly. Additionally, there are non-motor complications such as autonomic dysfunctions and psychiatric complications and cardiovascular side effects, which are supposed to be related to the metabolism of L-DOPA to norepinephrine (NE) and epinephrine. Direct DA agonists and selective DA reuptake inhibitors are the actual R&D mainstream and likely to become the drugs of first choice in the treatment of PD. However, there are still substantial questions to be answered. Within the next 10-15 years L-DOPA will remain an essential part of the PD therapy. BDD-206XX is a L-DOPA-like compound that emerged from the BDD/CCDRD Groupīs Atomic Substitution Technology platform and addresses current drawbacks of L-DOPA while simultaneously keeping all its advantageous features. With respect of its binding properties to various dopamine receptors, BDD-206XX-DA does not differ from endogenous DA. Administration of BDD-206XX in reserpine treated rats, an established PD animal model, leads to a significant increase in locomotor activity compared to classical L-DOPA treatment. Due to the higher efficacy of BDD-206XX-DA a reduced daily dose of BDD-206XX for the therapy of PD patients is expected that will diminish the overall catecholamine load and is unambiguously beneficial for long-term treatment. Furthermore, the rate of neuronal biodegradation of BDD-206XX-DA to NE is reduced to about 40% as compared to endogenous DA. From our experience with the atomic substitution technology we expect BDD-206XX to exhibit an improved passage through the blood-brain barrier and to be more resistant to oxidation than endogenous DA. Thus, BDD-206XX might lead to a diminished risk of long-term pro-degenerative effects due to iatrogenic cytosolic excess of autoxidative products of catecholamines. Overall, BDD-206XX is likely to exhibit in higher efficacy for PD treatment, less acute NE associated side effects and less oxidative neurotoxicity as compared to current L-DOPA. A 3rd generation 'perisone' and an appropriate formulation for improved treatment of acute back pain and spasticity
Development status: Preclinical
Description: Lower back pain is a disabling condition that is difficult to treat effectively. The standard therapy for lower back pain involves the use of NSAIDs together with muscle relaxants, with specific analgesics being added in the case of severe pain. Tolperisone-HCl, the prototype of the 'perisones' was introduced into Hungary by Gedeon Richter, is marketed successfully in Japan by a couple of companies, and is market leader for treatment of back pain in Germany. Advantageous features of Tolperisone include a low adverse event profile, a lack of sedation and no interaction with alcohol as well as no potential for tolerance and addiction. However, Tolperisone, which nowadays is generic compound, still has several pharmacological limitations, mainly a high first pass effect in various species which requires high daily doses for compensation and a metabolism which is dependent on the genetic background of the patients and thus open for a considerable interindividual pharmacokinetic variation. BDD-10103 is a Tolperisone-like compound that emerged from the BDD/CCDRD Groupīs Atomic Substitution Technology platform and addresses current drawbacks of Tolperisone by simultaneously keeping all its advantageous features. Various animal models confirmed that oral doses of BDD-10103 are more potent than the corresponding doses of Tolperisone both in selected preclinical rodent and non-rodent animal models: BDD-10103 and Tolperisone inhibited the monosynaptic ventral root reflex roughly to the same extent. However, BDD-10103 showed superiority in the tremorine test in mice after oral administration. Metabolic degradation of BDD-10103 and Tolperisone was assessed in hepatic liver microsomes. The results indicated that longer elimination half life can be expected for BDD-10103 in man than that published for Tolperisone. BDD-10103 follows a typical CYP 2D6, CYP 2C19 metabolism as does Tolperisone. The compound is however more stable against biodegradation by liver enzymes of the CYP family. Interestingly, formation of certain metabolites that occurred in the course of plain tolperisone biodegradation is suppressed within the BDD-10103 metabolism. Interestingly, a first pharmacokinetic study in man revealed an enhanced overall bioavailability of BDD-10103 compared to tolperisone. Pharmaceutical development includes the evaluation of an improved oral formulation to enhance the bioavailability of BDD 10103 in the human body. An improved Sildenafil-like compound for treatment of Erectile Dysfunction
Development status: Preclinical
Description: Sildenafil is a selective and potent inhibitor of phosphodiesterase 5 (PDE5) and used for the treatment of Erectile Dysfunction (ED). PDE5 is the predominant isoenzyme that metabolizes cGMP in the corpus cavernosum of the penis. cGMP plays a central role in penile vascular and corpus cavernosal smooth muscle relaxation. Relaxation of the penile vasculature allows blood to fill in sinusoidal spaces, thereby causing erection. Therefore, inhibition of PDE5 by Sildenafil leads to high levels of cGMP and reinforces penile erection. However, Sildenafil still exhibits some disadvantages, like the simultaneously potent inhibition of PDE6, leading adverse side effects like abnormal color vision and brightness during the peak plasma concentrations. Furthermore, a short elimination half-life of approximately 4 hrs is a limiting factor for sexual intercourse. BDD104XX is a Sildenafil-like compound that emerged from the BDD/CCDRD Groupīs atomic substitution platform and addresses current drawbacks of Sildenafil by simultaneously keeping all advantageous features of the prototype drug Sildenafil. BDD-104XX has a better selectivity for PDE5 in clinically relevant concentrations whilst inhibiting PDE6 to a lower extent when compared to Sildenafil. Furthermore, in an ex vivo rabbit corpus cavernosum contractility assay the concentration needed for 50% relative relaxation was lower for BDD104XX as compared to Sildenafil, indicating higher efficacy. From our experience with Atomic Substitution Technology we additionally expect improved pharmacokinetics as compared to the short elimination half-time of Sildenafil. The development of BDD-104XX aims at an improved Sildenafil-like active pharmaceutical ingredient (API) in a specific formulation which is effective in Erectile Dysfunction, and is characterized by a prolonged elimination half life, an improved absolute bioavailability, an improved penetration to site of action, a higher overall efficacy, an improved safety profile, and a reduced daily dose as compared to Sildenafil. The IP-protected approach allows to open up further indications. An imporved Melatonin-like compound with prolonged action for treatment of Insomnia
Development status: Preclinical
Description: Approximately 30% of the population experiences symptoms of insomnia on a regular basis, although at present only a fraction of patients are diagnosed, with even fever receiving prescribed pharmacological therapy. However, the insomnia market due to enhanced public awareness is expected to significantly expand over the next ten years. There are several unmet needs in the current insomnia market which primarily include the efficacy of the drug and the side effects leading to cognitive and dynamic function of patients. One of the major challenges is to develop a drug that induces sleep quickly, helps individuals remain asleep and allows them to awaken feeling refreshed rather than hung over. Melatonin, a hormone naturally synthesized in the pineal gland, has a central role within the regulation of the circadian system and sleep patterns in humans. Furthermore, insomnia in the elderly is highly associated with reduced Melatonin levels. Exogenous Melatonin is known to have a considerable potential for sleep induction and sleep prolongation, especially in the elderly. However, although from the extensive experiences of its use as a food supplement for a variety of purposes (mainly in the US) it can be regarded to be safe in humans even at high doses, it was never developed as a drug. This is due to several limitations, including the lack of possibility for patent protection and unfavourable kinetics of plain Melatonin in humans. The development of BDD-40001 as a new API for treatment of Insomnia aims to overcome these limitations by providing patent protection on the use of the API for treatment of Insomnia, combined with optimized pharmacokinetics in humans and a safety profile compareble to plain Melatonin. The lead compound BDD-40001 was specifically designed to exhibit enhanced metabolic stability as compared to plain Melatonin while maintaining its pharmacodynamic properties at the receptor sites. It was shown to be highly comparable to plain Melatonin in terms of melatonin receptor 1 and 2 binding and activation. From our experience with Atomic Substitution Technology platform we expect a significantly prolonged plasma half-life in humans. An improved Rofecoxib-like, selective COX-2 inhibitor for optimized treatment of canine osteoarthritis and postsurgical pain.
Development status: Preclinical
Description: NSAIDs (Non-steroidal anti-inflammatory drugs), the same class as such OTC remedies as Advil (ibuprofen), Orudis (ketoprofen) and aspirin in the US are in use in dogs mainly for pain relief, usually joint pain or post-surgical pain relief. The problem with this class of drugs has been unacceptable (even life-threatening) side-effects. Problems have in the past been related to stomach ulceration, platelet deactivation, and decreased blood supply to the kidneys. The veterinarian profession has been in the need of an NSAID that could effectively relieve pain without the above risks. The key appears to lie with the enzyme responsible for many inflammatory mediators, Cyclo-Oxygenase-2 (COX-2). A different but related enzyme, COX-1, is important for producing important biochemicals needed to maintain normal blood supply to the kidneys and GI tract. Till 1997 there were no compounds approved for dogs which inhibited COX-2 without inhibiting COX-1, hence the side effects of previous NSAIDS. The selective COX-2 inhibitors were introduced as alternatives to common non-selective NSAIDs in the treatment of arthritis. The lack of concomitant COX-1 inhibition promised to generate less adverse events especially in the gastrointestinal tract compared to non-selective COX inhibitors. Despite this could be confirmed, the cost-benefit ratio compared to non-selective NSAIDs did not justify a total switch to the COX-2 selective compounds, especially since it turned out that a simple positioning of the COX-2 selective APIs as NSAIDs with less side effects was not completely true. Rofecoxib (Vioxx) was withdrawn from the market for the use in humans, because of an observed increase in myocardial infarction and stroke at long-term treatment (>=18months) especially in patients with elevated risk factors (e.g. hypertension). The development of BDD-11602-vet aims at the development of an improved Rofecoxib-like active pharmaceutical ingredient (API) in a specific formulation which is effective in canine osteoarthritis and postsurgical pain, and is characterized by a superior COX-2 selectivity, a higher overall efficacy, a smaller daily dose, an improved safety profile, and/or pharmacokinetic advantages, and/or improved absolute bioavailability as compared to existing treatments for canine osteoarthritis and postsurgical pain (Carprofen, Deracoxib). |
