LITMUS Molecular Design - Executive Summary of New Antipsychotic Drug Portfolio
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College Neuropsychopharmacology Poster
LITMUS Molecular Design, LLC, a subsidiary of LITMUS, LLC, is in the business of analyzing existing molecular entities and discovering and developing new molecular entities for the pharmaceutical, chemical and materials science industries. Spectral Data Activity Relationship (“Spectral ModelingTM”) is a computational chemistry method used for drug design and optimization developed at FDA under a Collaborative Research and Development Agreement with LITMUS, LLC. LMD holds exclusive worldwide rights to the commercialization and development of the technology licensed from the FDA. Spectral ModelingTM utilizes computer-based mathematical methods to analyze spectral data for identification of spectral attributes that are highly predictive of a molecule’s biological, chemical, and physical activities. Further development and refinement of computational techniques has allowed LMD to extend the application of Spectral ModelingTM to design new chemical entities (NCE) with targeted activities (e.g., improved efficacy and reduced toxicity).
Despite tremendous efforts by the pharmaceutical industry to find antipsychotic drugs with satisfactory efficacy and minimal side effects, current agents have serious limitations in both regards. Atypical antipsychotic drugs, of which clozapine is the prototype and perhaps the most efficacious, may produce insulin resistance with weight gain, hyperglycemia, and increased lipids. The hypothesis that the atypical properties of clozapine, a drug with an enormous range of receptor affinities, are due to more potent serotonin (5-HT2A) than dopamine (DA) D2 receptor affinities has produced a number of compounds with similar profiles that have proven to be atypical antipsychotics. However, each of them has significant side effects (e.g., hyperprolactinemia associated with risperidone, marked weight gain with olanzapine, QTc prolongation with ziprasidone). This unmet medical need provides an opportunity for an improved antipsychotic drug to significantly penetrate the $18 billion global antipsychotic market.
Spectral ModelingTM was used to create new antipsychotic drug candidates, to optimize those candidates for efficacy, and to reduce side effects. 259 novel atypical antipsychotic drug candidates were designed to have desirable efficacy (based on the 5-HT2A/D2 model) and toxicity characteristics for the treatment of schizophrenia. These 259 drug candidates were generated from functional group substitutions on 5 novel chemical genera. Broad composition of matter patents have been filed for all 259 drug candidates. Three of the 259 new drug candidates were synthesized and their chemical structure and biological activity confirmed via chemical analysis, and in vitro and in vivo testing. LMD desires to rapidly monetize these new drug candidates via an out-license option agreement, or other business models as may be appropriate.
When screened against the spectral models, 204 of the 259 new drug candidates are predicted to have antipsychotic activity and 43 to have desirable receptor-binding profiles for atypical antipsychotic activity. Of these 43 atypical antipsychotic drug candidates, 3 were selected for synthesis and in vitro and in vivo testing. The affinities of two of these compounds for multiple G-protein-coupled-receptors were determined by the NIMH Psychoactive Drug Screening Program and their greater affinity for 5-HT2A receptors than DA D2 receptors confirmed.
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Two of these compounds were then studied using microdialysis in awake freely moving rats to determine their similarity to clozapine and other multireceptor 5-HT2A/D2 antagonists. One of the compounds, LMD-00076, produced a dose-dependent increase in cortical DA efflux which was blocked by the 5-HT1A silent antagonist, WAY 100635, as is the case with clozapine. WAY 100635 has been shown to block clozapine’s reversal of antipsychotic-induced catalepsy. LMD-00076 produced a modest increase in nucleus accumben dopamine release that exhibited a ceiling effect where increasing dose did not produce additional transmitter release. LMD-00076 also produced a significant increase in cortical acetylcholine (ACh) efflux, as do direct acting 5-HT2A/D2 antagonists. Increases in cortical ACh efflux are associated with positive effects on cognitive function. A second compound, LMD-00100t, produced a significant increase in cortical DA, but at the maximum dose tested, did not increase cortical ACh efflux. This pattern resembles aripiprazole.
These findings show that LMD-00076 produced neurotransmitter release patterns similar to those of clozapine in a rigorous animal model of atypical antipsychotic activity. LMD-00076 also showed activity on norepinephrine transport in a receptor binding assay. This effect at the norepinephrine transporter suggests that LMD-00076 may possess anti-depressant activity. In vivo tests for antidepressant activity are currently underway. A compound with positive cognitive effects and antidepressant activity could be particularly useful in the treatment of schizoaffective disorders and in treatment of Parkinson’s and Alzheimer’s patients. A second compound, LMD-00100t, produced neurotransmitter release patterns resembling aripiprazole’s. It is interesting to note that in the D2 receptor-binding affinity spectral model, the partial agonists aripiprazole and bifeprunox were predicted as very weak antagonists, which is how they would appear from the standpoint of antagonism. LMD-00100t is predicted to be a very weak D2 antagonist per the D2 receptor-binding model (Kd value > 1200 nM) and is proportionally less potent in vivo. These activities are consistent with their receptor binding affinities.
The compounds studied to date proved to be biologically active in a rigorous model which distinguishes typical from atypical antipsychotic drugs. Further testing of these compounds in classical models of antipsychotic activity and extrapyramidal side effects in laboratory animals is in progress, along with studies of their ability to reverse the effects of phencyclidine on novel object recognition.
LMD is also in the process of creating other drug candidates in other therapeutic categories. For example, LMD has also created a group of 103 HSP-90 inhibitors as drug candidates in the treatment of breast cancer, and a group of 64 orexin 1 receptor antagonists for multiple disorders.
Also, visit www.litmusmoleculardesign.com for in-depth technical information and white papers on Spectral Modeling™