Recent patent applications for small molecule serotonin modulators

[JacksinPA]

PYRAZOLE DERIVATIVES AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO

https://www.google.com/search?tbo=p&tbm=pts&hl=en&q=patent:20170320831&num=10

Abstract
Pyrazole derivatives of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the serotonin 5HT.sub.2A receptor. Formula (Ia). Compounds and pharmaceutical compositions thereof are directed to methods useful in the treatment of insomnia and related sleep disorders, platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, reducing the risk of blood clot formation, asthma or symptoms thereof, agitation or symptoms thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorders, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, diabetic-related disorders, progressive multifocal leukoencephalopathy and the like. The present invention also relates to the methods for the treatment of 5-HT.sub.2A serotonin receptor mediated disorders in combination with other pharmaceutical agents administered separately or together. ##STR00001##
Inventors: Xiong; Yifeng; (San Diego, CA) ; Cherrier; Martin C.; (Chicago, IL) ; Choi; Jin Sun Karoline; (San Diego, CA) ; Dosa; Peter I.; (San Diego, CA) ; Smith; Brian M.; (San Diego, CA) ; Strah-Pleynet; Sonja; (Newton, MA) ; Ullman; Brett; (San Diego, CA) ; Teegarden; Bradley; (San Diego, CA)
Applicant: Arena Pharmaceuticals, Inc.
San Diego, CA

 

[JacksinPA]

United States Patent Application	20170319580
Kind Code	A1
YAO; Wei ; et al.	November 9, 2017

[SIZE=+1]ORGANIC COMPOUNDS

[/SIZE]https://www.google.com/search?hl=en...j2.64.psy-ab..0.1.87...0j0i67k1.0.KQCl5kXjaTI

AbstractThe invention relates to particular substituted heterocycle fused gamma-carbolines, their prodrugs, in free, solid, pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving the 5-HT.sub.2A receptor, the serotonin transporter (SERT), pathways involving the dopamine D.sub.1 and D.sub.2 receptor signaling system, and/or the .mu.-opioid receptor.

Inventors:

YAO; Wei; (New Milford, NJ) ; LI; Peng; (New Milford, NJ) ; DAVIS; Robert; (San Diego, CA) ; MATES; Sharon; (New York, NY) ; VANOVER; Kimberly; (New York, NY) ; SNYDER; Gretchen; (New York, NY)

Applicant:	Name City State Country Type INTRA-CELLULAR THERAPIES, INC. New York NY US
Family ID:	1000002776166
Appl. No.:	15/660615
Filed:	July 26, 2017

 

[JacksinPA]

United States Patent Application	20170283417
Kind Code	A1
LI; Peng ; et al.	October 5, 2017

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[SIZE=+1]ORGANIC COMPOUNDS [/SIZE]

AbstractThe invention relates to particular substituted heterocycle fused gamma-carbolines, their prodrugs, in free, pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving 5-HT.sub.2A receptor, serotonin transporter (SERT) and/or pathways involving dopamine D.sub.2 receptor signaling systems.

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Inventors:

LI; Peng; (New Milford, NJ) ; ZHANG; Qiang; (Plainsboro, NJ) ; DAVIS; Robert; (San Diego, CA) ; Wennogle; Lawrence P.; (Hillsborough, NJ)

Applicant:	Name City State Country Type INTRA-CELLULAR THERAPIES, INC. New York NY US
Assignee:	INTRA-CELLULAR THERAPIES, INC. New York NY
Family ID:	1000002692982
Appl. No.:	15/629481
Filed:	June 21, 2017

 

[Weltmeister]

Have there been any papers published on any of these substances yet ?

 

[5ht2Antogonist]

Can somebody explain what's this all about? So.. maybe they've found that 5ht2a receptor is the most important one affecting CNS disorders?

 

[sekio]

Presumably these are novel haloperidol-type antipsychotics.

The patent description text is purposefully written to cover as many possible utilities of the compound as possible in order to maximize likelihood that the patent will be licensed for one use or another. Same reason there's dozens of similar looking analogs, in reality perhaps only one or two compounds per patent are going to be exhaustively tested as clinical candidates, the trick is figuring out which ones exactly. Maybe there's some that have better selectivity, better tox profile, better BA or half life, than others.

 

[browri]

I've been following ICTI for a while now and they're coming out with some interesting stuff. These compounds appear structurally similar to their principal compound right now ITI-007, lumateperone.

5HT2A antagonist (0.54nM)


D2S partial agonist and D2L antagonist (32nM)


D1 antagonist (52nM)


SERT blocker (61nM)


α1A antagonist (73nM)


5HT2C antagonist (173nM)

1. It fully saturates 5HT2A at the bottom of the dose range with little effect at that point on other targets. Because of how sedating that effect can be, they plan on marketing it on the low-end of the dose range (10-20mg) for sleep disturbances related to a wide range of psychiatric conditions like depression (MDD and BP) as well as agitation in dementia. Would be particularly useful for SSRI-induced insomnia.


2. At the middle of the dose range (40-60mg) you can modulate dopamine receptors and the serotonin transporter, at this point getting into the range of antipsychotic and antidepressant efficacy. They found in trials that lumateperone did improve both positive and negative symptoms of schizophrenia as well as social outcomes, which is something that not many APs can boast.


3. They are trialing it in bipolar depression, although I don't think they're trying for the MDD adjunct yet simply because lumateperone does already work on SERT.


4. In regards to tolerability and safety, they did two studies with risperidone as the active comparator. Where risperidone at 4mg obviously caused considerable metabolic disturbances and prolactin elevation, lumateperone at 60mg did neither, or if it did it wasn't statistically significant when placebo was also considered.


5. Most antipsychotics need 75%-90% dopamine receptor occupancy to properly exert antipsychotic effect. And that's very close to the occupancy that would cause movement-related side effects and prolactin elevation (85%+). Lumateperone at 60mg resulted in D2 receptor occupancy between 50% and 70%, while still demonstrating similar antipsychotic efficacy to established therapies and simultaneously having significantly reduced incidence of AEs, particularly ones that led to patients discontinuing the study.


6. At this point in time, of all the (traditional) antipsychotics, clozapine has the highest ratio of 5HT2A/D2 (although technically amoxapine is higher but isn't TRADITIONALLY an antipsychotic). This would be followed by asenapine, risperidone (12-fold higher), and olanzapine (12.4 fold higher). Lumateperone's ratio is a 60-FOLD HIGHER affinity for 5HT2A over D2. Meaning with total saturation of 5HT2A receptors at all doses, the release of dopamine in the nigrostriatal areas of the brain should be enough to mitigate against EPS and prolactin elevation even at higher dopamine receptor occupancies.


7. However, believe it or not, the 120mg dose didn't fair better than comparators or placebo particularly on negative symptoms. It would seem this kind of makes it similar to lurasidone or lamotrigine where for bipolar disorder and bipolar depression in particular the lower end of the dose range is useful but the top end really isn't helpful, might make things worse, and usually just results in side effects.


8. Intra-Cellular Therapies is placing particular emphasis on the D1 receptor activity as well because of its downstream enhancement of glutamatergic neurotransmission and subsequent activation of NMDA and AMPA receptors, particularly iGluNR2B. As an aside to this, the D1 receptor has been implicated in OCD, which is why low doses of clozapine are sometimes used in treatment-resistant OCD. Its metabolite norclozapine has an affinity at that receptor of about 14nM, which is bested only by asenapine (1.4nM).


9. This will be the very first antipsychotic that has a different action at the D2 receptors based on receptor location. Always blocking the post-synaptic receptors but either activating or blocking the pre-synaptic receptors based on dopamine levels. I can't remember where I read this but I'm pretty sure lumateperone's IA at D2S is 20-40%. So not much activating activity, but perhaps JUST ENOUGH to slow down the dopamine pump. Additionally, lumateperone appears to be preferential to the mesocortical/mesolimbic areas vs the striatum which may contribute to the almost relative lack of EPS in trials compared to riperidone. Would also explain the lack of prolactin elevation.


10. Very low affinity for 5HT2C should lead to less weight gain, while still having a minor positive affect on mood. And of course, low-to-moderate α1A antagonism is always useful in schizophrenia and anxiety disorders.

They look to be on track for FDA approval in 2nd half of this year. They received Fast-track designation, which MIGHT speed things up.

The other compound they're working on is ITI-333, but it hasn't reached Phase I yet. Still pre-clinical. It works specifically on 5HT2A, D1, and mu-opioid receptors. They're researching it for substance use disorder, depression, and pain. Clearly these guys have been chatting with Alkermes.