The most common approach for treating any CNS disorder, including Fragile X syndrome, involves modulation of the complex array of neurotransmitters and receptors that are in homeostasis in the healthy human brain, but become unbalanced in a disease state. The neurotransmitter serotonin (5-hydroxytryptamine, 5HT) and its multiple receptor subtypes play a central role in normal brain function. This critical system has been the focus of decades-long drug research that has yielded commercially successful drug classes for treating depression, anxiety and other mental disorders. Importantly, it is now known that disruption in serotoninergic neurotransmission plays a prominent role in Fragile X syndrome. However, there were two big challenges in pursuing this approach:

  • Identifying which receptor subtypes need to be modulated (stimulated or inhibited) to effectively treat the disorder.
  • Finding drug molecules that selectively interact only with those receptors.

Previous work in this area has shown that selective receptor modulation is very difficult to achieve. Lack of selectivity is a problem with virtually all current CNS drugs, which leads to a wide range of significant side effects.

Seropeutics is taking a targeted approach in the development of drugs to treat Fragile X syndrome with the goal of ‘threading the needle’ with respect to achieving high target selectivity and appropriate function, with minimal off-target receptor binding that can lead to side effects. Our strategy has been to use structure-based drug design to identify selective modulators of key 5HT (serotonin) receptors believed to be involved in mediating Fragile X symtoms and test them in validated animal models for predicting therapeutic efficacy. What have emerged from our program are two distinct, first-in-class drug series that display high selectivity against different receptor types:

Preclinical evaluation of our SERx – 500 and SERx – 400 series  has confirmed that both have favorable pharmacological profiles:

  • High target/off-target selectivity,
  • therapeutic efficacy in multiple animal models with oral dosing
  • Extensive PK/metabolic profiling data
  • Crosses the blood brain barrier
  • No toxicity observed to date in animal studies suggesting that favorable toxicity profile may be achieved

Chemistry is in place for scale-up to support advanced studies of both candidates.

SERx – 500 Series

Our SERx – 500 series chemotype has a unique profile with 5HT1A, 5HT2C, and 5HT7 receptor partial agonist activity. Our lead compound, SERx – 519, is highly effective in decreasing repetitive behaviors and motor stereotypy, and increasing social functioning in multiple Fragile X syndrome and autism mouse models, suggesting efficacy in treating core Fragile X symptoms. Partial activation of 5HT1A receptors alleviates stereotyped (repetitive) behaviors and social anxiety, while partial activation of 5HT2C and 5HT7 receptors produces pro-cognitive effects. Importantly, we have achieved this high 5HT1A/2C/7 selective activation with minimal effects at other receptors, which represents a unique receptor modulation profile—no other drug class achieves this. We anticipate that our lead will have minimal side effects, such as suppression of locomotor activity, sedative/stimulant activity, or cognitive impairment seen with other drugs.

We have evaluated the SERx – 519 in multiple animal models:


SERx – 519 attenuates (abolishes) repetitive jumping in mouse models of Fragile X syndrome and autism spectrum disorder.

SERx – 519 has no detectable effect on normal locomotor behavior in FXS/ASD (C58J) or Wild-type (C57J) mice.

SERx – 519 attenuates effects of dizoclipine (MK801), a glutamate antagonist that induces repetitive circling behavior and cognitive dysfunction in mice.

SERx – 519 attenuates effects of dimethoxyiodoamphetamine (DOI), a serotonin agonist that induces repetitive head-twitching in mice.

SERx – 519  increases social behaviors and decreases unproductive compulsive behaviors (obsessive grooming) in mice.

A head-to-head comparison of SERx – 519 vs. buspirone was conducted.  SERx – 519, like buspirone, attenuates repetitive behavior in a mouse model of tics/head-twitch.  However, in contrast to buspirone, SERx – 519 does not significantly depress locomotor activity (no sedative effect).

SERx – 400 Series

We have also developed a SERx – 400 series that exhibits a different, but complementary, pharmacological profile that has potential for treating additional symptoms that often accompany Fragile X syndrome and other autistic disorders. Our SERx – 400 series selectively enhances 5-HT2C signaling while reducing 5-HT2A/2B signaling. As with our SERx – 500 series, this represents a first-in-class pharmacological profile and we believe that our SERx – 400 lead, SERx  480, has potential to address cognitive dysfunction, attention deficit, hyperactivity, and psychosis associated with Fragile X syndrome and autism. We anticipate that SERx  480 will not produce the sedative or weight gain side effects that typically accompany other antipsychotic drugs frequently used in Fragile X patients.


SERx -400 series balanced neuromodulatory activity (5HT2C activation, 5HT-2A/2B inactivation)  translates to beneficial effects on memory, learning, and cognitive function.


SERx – 400 Series: First-in-Class 5-HT2C Agonist with 5-HT2A/2B Inverse Agonist Activity

SERx – 480 demonstrates efficacy in an in vivo mouse model of hallucinogen psychosis.

SERx drug candidates have activity to reduce impulsive and compulsive behaviors that frequently occur in Fragile X syndrome. For example, SERx –480 blocks impulsive/compulsive behavior in a mouse binge-eating model (Journal of Pharmacology and Experimental Therapeutics 2014, Vol 349, pages 310-318).

In contrast to other antipsychotic drugs, including, aripiprazole that is used to treat irritability in autism spectrum disorder, SERx – 480 demonstrates no sedative effect in an in vivo mouse model of sedation.

In rodent model of obsessive-compulsive disorder cognitive impairment (ADHD), SERx-480 selectively increases attention (observing response vs. food response), similar to amphetamine. Our SERx-400 series compounds are as effective as amphetamines in the ADHD mouse models and they have a significantly improved safety profile.


Representative SERx compounds were submitted to the National Institutes of Health subcontractor CROs to delineate absorption, distribution, metabolism, and toxicity (ADMET) parameters. Evaluation at 50 CNS/peripheral sites indicate low (Ki > 1 mM) or nil (Ki > 5 mM) affinity for adenylyl cyclase, adenosine, adrenergic, benzodiazepine, cholinergic, dopamine, GABAA, hERG, histamine; opiate, NMDA, PCP, PLC, sigma, DAT, NET, SERT, ion channels (Ca++, Cl, K+). Functional studies indicate hERG activity is nil (IC50 > 2.0 µM), thus, no cardiotoxicity is expected; our own results document no activation of 5HT2B GPCRs (no cardiotoxicity). DAT functional activity also was nil. The inhibitory effects on CYP activity in human liver microsomes was measured for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4—no inhibition was observed at 10 µM. Also, no toxicity was observed to human hepatocyte Fa2N-4 cells. Incubation at 10 and 100 µM with rat, rabbit, dog, monkey, and human liver microsomes indicated predictable N,N-dealkylated and aromatic hydroxylated metabolites. Leads are currently scheduled to undergo GMP IND-enabling ADMET studies by Aptuit LLC (Verona, Italy).

In vivo pharmacokinetics: SERx chemotypes are orally active in rodent models of autism spectrum disorder, psychoses, schizophrenia, addiction (psychostimulants, ethanol, opioids) and other compulsive behavioral disorders such as binge-eating. For example, SERx – 519 is neurobehaviorally active after oral administration for at least 3-hours; 1-2 µg levels in mouse brain at 30, 60, and 90 min (plasma levels at 10% of brain levels for all time points)

Below is the data for SERx – 519 taken from lead paper. Canal CE, Felsing DE, Liu Y, Zhu W, Wood JT, Perry CK, Vemula R, Booth RG. An Orally-Active Phenylaminotetralin-Chemotype Serotonin 5-HT7 and 5-HT1A Receptor Partial Agonist that Corrects Motor Stereotypy in Mouse Models. ACS Chem Neurosci. 2015; 6:1259-1270. PMID:26011730.



Intellectual Property

Seropeutics holds broad intellectual property rights to both the SERx – 500 and SERx – 400 series with multiple issued patents, applications and anticipated filings.

University of Florida IP: 3 Families

  • Patents/Patent Applications Based on PCT/US2008/007458
    • Patents covering methods of treatment with genus of SERx – 400 series granted in US, Europe and Japan. Further application pending in US with composition claims. Life of patents is to 2028 (clinical trial extension to 2031)
  • Patent Applications Based on PCT/US2008/007457:
    • Covers SERx – 500 series compounds; Natural life of patents is to 2028; Allowable composition claims in US
  • Patent/Patent Applications Based on PCT/US2010/00133:
    • Natural life of patents is to 2030; Granted in US with claims to a genus of SERx – 400 series. Applications pending in US, Europe, and Japan.

Northeastern University IP: 2 Families

  • Applications to be filed from PCT/US15/31523
    • Discloses specific SERx – 500 series lead compounds,  animal studies confirming utility, as well as uses of SERx – 500 series to treat stereotypy. Can be nationalized broadly in Q4, 2016. Life of patents is 2035
  • Applications to be filed from US Provisional 62/163,652
    • Discloses further compounds with specific biodistribution features for GI pathologies. Can be nationalized broadly in Q4, 2017. Natural life of patents is to 2036.