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#1 - A novel compound for treatment of disorders with cognitive dysfunction for example attention-deficit/hyperactivity disorder
Long Title: Modified Modafinil to enhance selectivity and solubility for the treatment of addiction, attention disorders and/or sleep-related disorders.
NIH Reference No.: E-073-2013
Executive Summary:
General Description
Modafinil (2-[(diphenylmethyl)sulfinyl]acetamide, Provigil®) is a non-addictive drug approved by the FDA for treatment of sleep and wakefulness disorders such as narcolepsy or shift work sleep disorder. Modafinil is used as a stimulant to promote vigilance and reduce sleepiness. Clinical data supports its main function as a dopamine (DA) reuptake inhibitor, which binds directly to the DAT with a similar mechanism to methylphenidate (Ritalin). Due to this mechanism the drug has also been suggested as a viable option to treat ADHD as well as psychostimulant substance abuse, however it failed in clinical trials for cocaine and methamphetamine addiction, despite early clinical promise. Modafinil is prescribed off-label to treat ADHD, but is not approved by the FDA for this use.
To improve Modafinil’s therapeutic efficacy, researchers undertook a study to modify the Modafinil drug through structure-activity relationship (SAR) analysis of the generated collection of chemical derivatives. They tested, both separately and in combination, alkyl substitutions to the terminal amide, halogen substitutions of the diphenyl rings, reduction of the S=O motif, and removal of the carbonyl (C=O) motif. In their experiments they monitored water solubility, metabolism, pharmacokinetics (PK), blood brain barrier (BBB) penetration and binding affinities to all three monoamine transporters i.e. DAT, serotonin (SERT), and norepinephrine (NET), in rat brain membranes, as well as other off targets that may adversely affect the translation of these compounds into the clinic (e.g. hERG channel).
Scientific Progress
In a previous study the researchers replaced the terminal amide of Modafinil with a 3-phenylpropyl-substituted amine group and observed a 10-fold increase in binding affinity to DAT as well as improved water solubility. In a more recent publication they describe an expanded SAR study by substituting both the terminal amide, and the diphenyl rings, with different chemical moieties as well as a reduction of the terminal amide to the amine, which strongly improves affinity to DAT and solubility in water. They also noticed that the substitution of the diphenyl rings with halogens (F-, Cl- or Br-) generated amide analogues with improved sensitivity for DAT over SERT and NET, in addition to several amine analogues with much higher and improved affinity for SERT (Ki ≤ 30 nM). Additional studies comparing the modified Modafinil compounds to mutants of DAT (A480T) and SERT (T497A) in cell-based studies further confirmed their findings and have led to hypotheses of drug-protein interactions at the molecular level that may lead to an improved therapeutic profile for these agents. Selected analogues have now been evaluated for metabolic stability in liver microsomes, BBB penetration, i.v. and oral PK, locomotor behavior and effects on cocaine self administration, as well as measurements of dopamine levels in the nucleus accumbens shell via microdialysis. These preliminary studies point to an atypical DAT inhibition profile that suggests these compounds will have therapeutic utility without addictive liability. Drug-like enhancements to further improve dosing regimens over that of the parent drug are underway.
Future Direction
Strengths
Weaknesses
Patent Status
US Provisional Application No. 61/774,878 filed on March 8, 2013
PCT application filed on March 7, 2014
Relevant Publications
Okunola-Bakare OM et al.,J Med Chem. 2014 Feb 13;57(3):1000-13. [PMID:24494745]
Cao J, et al., ACS Med Chem Lett. 2010 Oct 10;2(1):48-52. [PMID:21344069]
Inventor Bio
Amy Hauck Newman, Ph.D.
Dr. Newman received her Ph.D. in medicinal chemistry from the Medical College of Virginia, where she designed, synthesized and behaviorally evaluated novel amphetamine analogues. During postdoctoral training at NIDDK, she expanded her experience with opiate total synthesis and developed PET ligands for opioid receptor imaging. After a short tenure at Walter Reed Army Institute of Research, she initiated a Medicinal Chemistry Program at NIDA. Her research focuses on the design and synthesis of molecular tools to elucidate drug-receptor interactions in the brain and induce changes at the protein level to affect behavior. Dr. Newman is currently studying the roles of the dopamine and serotonin transporters, the dopamine D2 receptor family, and mGluR5 in addiction, aiming to develop medications for treatment.
NIH Reference No.: E-073-2013
Executive Summary:
- Invention Type: Therapeutic
- Patent Status: US Application No. 61/774,878
- LINK: http://www.ott.nih.gov/technology/E-073-20130
- NIH Reference Number: E-073-2013
- NIH Institute or Center: National Institute on Drug Abuse (NIDA)
- Disease Focus: Attention Deficit disorders (e.g. ADHD, ADD); Sleep disorders (narcolepsy); psychostimulant substance abuse
- Basis of Invention: Chemical modifications of an existing drug to improve therapeutic specificity and enhance binding interactions with monoamine transporters.
- How it works: Halogen substitution of the diphenyl rings and modification of the amide function through substitution and/or reduction to the amine improves affinity for the inward facing conformation of the dopamine transporter (DAT) giving an atypical (non-addictive) pharmacological profile. Some modifications have significantly improved serotonin transporter (SERT) binding.
- Lead Inventor: Dr. Amy Hauck Newman (NIDA)
- Development Stage: Pre-clinical, in vitro assays, metabolism, PK and behavioral studies in rodents
- Novelty: A library of novel compounds with higher affinity for monoamine transporters and also an atypical profile that features desired therapeutic potential without addictive liability. These improvements may also allow for lower or less frequent dosing and improved bioavailability compared to the original compound
- Clinical Applications: treatment of attention deficit disorders (ADHD, ADD); sleep disorders (narcolepsy, shift work sleep disorder, sleep apnea) for which the current standard of care is Modafinil; treatment of psychostimulant drug abuse, such as cocaine, nicotine and methamphetamine
General Description
Modafinil (2-[(diphenylmethyl)sulfinyl]acetamide, Provigil®) is a non-addictive drug approved by the FDA for treatment of sleep and wakefulness disorders such as narcolepsy or shift work sleep disorder. Modafinil is used as a stimulant to promote vigilance and reduce sleepiness. Clinical data supports its main function as a dopamine (DA) reuptake inhibitor, which binds directly to the DAT with a similar mechanism to methylphenidate (Ritalin). Due to this mechanism the drug has also been suggested as a viable option to treat ADHD as well as psychostimulant substance abuse, however it failed in clinical trials for cocaine and methamphetamine addiction, despite early clinical promise. Modafinil is prescribed off-label to treat ADHD, but is not approved by the FDA for this use.
To improve Modafinil’s therapeutic efficacy, researchers undertook a study to modify the Modafinil drug through structure-activity relationship (SAR) analysis of the generated collection of chemical derivatives. They tested, both separately and in combination, alkyl substitutions to the terminal amide, halogen substitutions of the diphenyl rings, reduction of the S=O motif, and removal of the carbonyl (C=O) motif. In their experiments they monitored water solubility, metabolism, pharmacokinetics (PK), blood brain barrier (BBB) penetration and binding affinities to all three monoamine transporters i.e. DAT, serotonin (SERT), and norepinephrine (NET), in rat brain membranes, as well as other off targets that may adversely affect the translation of these compounds into the clinic (e.g. hERG channel).
Scientific Progress
In a previous study the researchers replaced the terminal amide of Modafinil with a 3-phenylpropyl-substituted amine group and observed a 10-fold increase in binding affinity to DAT as well as improved water solubility. In a more recent publication they describe an expanded SAR study by substituting both the terminal amide, and the diphenyl rings, with different chemical moieties as well as a reduction of the terminal amide to the amine, which strongly improves affinity to DAT and solubility in water. They also noticed that the substitution of the diphenyl rings with halogens (F-, Cl- or Br-) generated amide analogues with improved sensitivity for DAT over SERT and NET, in addition to several amine analogues with much higher and improved affinity for SERT (Ki ≤ 30 nM). Additional studies comparing the modified Modafinil compounds to mutants of DAT (A480T) and SERT (T497A) in cell-based studies further confirmed their findings and have led to hypotheses of drug-protein interactions at the molecular level that may lead to an improved therapeutic profile for these agents. Selected analogues have now been evaluated for metabolic stability in liver microsomes, BBB penetration, i.v. and oral PK, locomotor behavior and effects on cocaine self administration, as well as measurements of dopamine levels in the nucleus accumbens shell via microdialysis. These preliminary studies point to an atypical DAT inhibition profile that suggests these compounds will have therapeutic utility without addictive liability. Drug-like enhancements to further improve dosing regimens over that of the parent drug are underway.
Future Direction
- Test the improved compounds for toxicity and activity in preclinical animal models
- Test additional analogues in animals for attenuation of drug seeking behavior and for effects on attention, cognition and psychostimulant –induced sleep disorders
- Evaluate different modes of delivery
- Investigate slow release compositions allowing for long term maintenance of pharmacological concentration in the target tissue
- Continue developing Modafinil analogues to further explore the mechanism underlying the atypical DAT profile as well as to explore contributions of both SERT, and/or NET in the therapeutic utility of these agents for the treatment of addiction attention deficit disorders and/or sleep disorders.
Strengths
- Improved water solubility allowing for greater control of effective concentration in the target tissue
- Superior affinity and binding mechanism at the DAT (atypical profile) allowing for use of reduced doses of drugs, possibly limiting side effects.
- Enhanced selectivity for specific transporter minimizes off-target binding
Weaknesses
- Pre-clinical stage - still require completion of all phases of clinical trials before FDA approval and commercialization.
- Although safe in rodents at doses tested, toxicity is unknown
Patent Status
US Provisional Application No. 61/774,878 filed on March 8, 2013
PCT application filed on March 7, 2014
Relevant Publications
Okunola-Bakare OM et al.,J Med Chem. 2014 Feb 13;57(3):1000-13. [PMID:24494745]
Cao J, et al., ACS Med Chem Lett. 2010 Oct 10;2(1):48-52. [PMID:21344069]
Inventor Bio
Amy Hauck Newman, Ph.D.
Dr. Newman received her Ph.D. in medicinal chemistry from the Medical College of Virginia, where she designed, synthesized and behaviorally evaluated novel amphetamine analogues. During postdoctoral training at NIDDK, she expanded her experience with opiate total synthesis and developed PET ligands for opioid receptor imaging. After a short tenure at Walter Reed Army Institute of Research, she initiated a Medicinal Chemistry Program at NIDA. Her research focuses on the design and synthesis of molecular tools to elucidate drug-receptor interactions in the brain and induce changes at the protein level to affect behavior. Dr. Newman is currently studying the roles of the dopamine and serotonin transporters, the dopamine D2 receptor family, and mGluR5 in addiction, aiming to develop medications for treatment.
