GEPIRONE


Synonyms	Ariza BMY-13805 Gepirone ORG-13011 Variza
Status
Molecule Category	UNKNOWN
ATC	N06AX19
UNII	JW5Y7B8Z18
EPA CompTox	DTXSID90232813


Active Pharmaceutical Ingredients Bioactive chemicals	Exact Similarity SubStructure	Threshold (%) >= 70

Structure


InChI Key	QOIGKGMMAGJZNZ-UHFFFAOYSA-N
Smiles	CC1(C)CC(=O)N(CCCCN2CCN(c3ncccn3)CC2)C(=O)C1
InChI	InChI=1S/C19H29N5O2/c1-19(2)14-16(25)24(17(26)15-19)9-4-3-8-22-10-12-23(13-11-22)18-20-6-5-7-21-18/h5-7H,3-4,8-15H2,1-2H3

Physicochemical Descriptors

Property Name	Value
Molecular Formula	C19H29N5O2
Molecular Weight	359.47
AlogP	1.55
Hydrogen Bond Acceptor	6.0
Hydrogen Bond Donor	0.0
Number of Rotational Bond	6.0
Polar Surface Area	69.64
Molecular species	NEUTRAL
Aromatic Rings	1.0
Heavy Atoms	26.0

Reference

Journal : Bioorg. Med. Chem. Lett.

Title : The design and preparation of metabolically protected new arylpiperazine 5-HT1A ligands.

PubMed ID : 15026055

DOI : 10.1016/j.bmcl.2004.01.045

Year : 2004

Volume : 14

Issue : 7

First Page : 1709

Last Page : 1712

Authors : Tandon M, O'Donnell MM, Porte A, Vensel D, Yang D, Palma R, Beresford A, Ashwell MA.

Abstract : New arylpiperazines related to buspirone, gepirone and NAN-190 were designed and screened in silico for their 5-HT(1A) affinity and potential sites of metabolism by human cytochrome p450 (CYP3A4). Modifications to these structures were assessed in silico for their influence on both 5HT(1A) affinity and metabolism. Selected new molecules were synthesized and purified in a parallel chemistry approach to determine structure activity relationships (SARs). The resulting molecules were assessed in vitro for their 5HT(1A) affinity and half-life in a heterologously expressed human CYP3A4 assay. Molecular features responsible for 5-HT(1A) affinity and CYP3A4 stability are described.

Reference

Journal : J. Med. Chem.

Title : Structure-activity relationship studies of central nervous system agents. 5. Effect of the hydrocarbon chain on the affinity of 4-substituted 1-(3-chlorophenyl)piperazines for 5-HT1A receptor site.

PubMed ID : 1535661

DOI : 10.1021/jm00091a004

Year : 1992

Volume : 35

Issue : 13

First Page : 2369

Last Page : 2374

Authors : Mokrosz JL, Pietrasiewicz M, Duszyńska B, Cegła MT.

Abstract : The effect of the hydrocarbon chain of the model 4-substituted 1-(3-chlorophenyl)piperazines 12-31 on their affinity for 5-HT1A receptor sites was investigated. It was found that elongation of the 4-n-alkyl chain strongly increases the 5-HT1A affinity of the investigated compounds. The affinity reaches the maximum (Ki = 2.67 nM) for the n-hexyl derivative 20. It was shown that hydrophobic interactions of N-4 substituents of 1-arylpiperazines significantly contribute to their 5-HT1A affinity. The specific binding constant was defined as the receptor affinity of the protonated species of compounds under physiological conditions. The range of Ki(AH+) = 1 - 3 x 10(-11) M is a specific affinity limit of the investigated class of compounds at the 5-HT1A receptor sites.

Reference

Journal : J. Med. Chem.

Title : Arylpiperazine derivatives as high-affinity 5-HT1A serotonin ligands.

PubMed ID : 3172131

DOI : 10.1021/jm00118a018

Year : 1988

Volume : 31

Issue : 10

First Page : 1968

Last Page : 1971

Authors : Glennon RA, Naiman NA, Lyon RA, Titeler M.

Abstract : Although simple arylpiperazines are commonly considered to be moderately selective for 5-HT1B serotonin binding sites, N4-substitution of such compounds can enhance their affinity for 5-HT1A sites and/or decrease their affinity for 5-HT1B sites. A small series of 4-substituted 1-arylpiperazines was prepared in an attempt to develop agents with high affinity for 5-HT1A sites. Derivatives where the aryl portion is phenyl, 2-methoxyphenyl, or 1-naphthyl, and the 4-substituent is either a phthalimido or benzamido group at a distance of four methylene units away from the piperazine 4-position, display high affinity for these sites. One of these compounds, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (18), possesses a higher affinity than 5-HT and represents the highest affinity (Ki = 0.6 nM) agent yet reported for 5-HT1A sites.

Reference

Journal : J. Med. Chem.

Title : An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression.

PubMed ID : 16722631

DOI : 10.1021/jm0508641

Year : 2006

Volume : 49

Issue : 11

First Page : 3116

Last Page : 3135

Authors : Becker OM, Dhanoa DS, Marantz Y, Chen D, Shacham S, Cheruku S, Heifetz A, Mohanty P, Fichman M, Sharadendu A, Nudelman R, Kauffman M, Noiman S.

Abstract : We report the discovery of a novel, potent, and selective amidosulfonamide nonazapirone 5-HT1A agonist for the treatment of anxiety and depression, which is now in Phase III clinical trials for generalized anxiety disorder (GAD). The discovery of 20m (PRX-00023), N-{3-[4-(4-cyclohexylmethanesulfonylaminobutyl)piperazin-1-yl]phenyl}acetamide, and its backup compounds, followed a new paradigm, driving the entire discovery process with in silico methods and seamlessly integrating computational chemistry with medicinal chemistry, which led to a very rapid discovery timeline. The program reached clinical trials within less than 2 years from initiation, spending less than 6 months in lead optimization with only 31 compounds synthesized. In this paper we detail the entire discovery process, which started with modeling the 3D structure of 5-HT1A using the PREDICT methodology, and then performing in silico screening on that structure leading to the discovery of a 1 nM lead compound (8). The lead compound was optimized following a strategy devised based on in silico 3D models and realized through an in silico-driven optimization process, rapidly overcoming selectivity issues (affinity to 5-HT1A vs alpha1-adrenergic receptor) and potential cardiovascular issues (hERG binding), leading to a clinical compound. Finally we report key in vivo preclinical and Phase I clinical data for 20m tolerability, pharmacokinetics, and pharmacodynamics and show that these favorable results are a direct outcome of the properties that were ascribed to the compound during the rational structure-based discovery process. We believe that this is one of the first examples for a Phase III drug candidate that was discovered and optimized, from start to finish, using in silico model-based methods as the primary tool.

Reference

Journal : J. Med. Chem.

Title : An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression.

PubMed ID : 16722631

DOI : 10.1021/jm0508641

Year : 2006

Volume : 49

Issue : 11

First Page : 3116

Last Page : 3135

Authors : Becker OM, Dhanoa DS, Marantz Y, Chen D, Shacham S, Cheruku S, Heifetz A, Mohanty P, Fichman M, Sharadendu A, Nudelman R, Kauffman M, Noiman S.

Reference

Journal : J. Med. Chem.

Title : An integrated in silico 3D model-driven discovery of a novel, potent, and selective amidosulfonamide 5-HT1A agonist (PRX-00023) for the treatment of anxiety and depression.

PubMed ID : 16722631

DOI : 10.1021/jm0508641

Year : 2006

Volume : 49

Issue : 11

First Page : 3116

Last Page : 3135

Authors : Becker OM, Dhanoa DS, Marantz Y, Chen D, Shacham S, Cheruku S, Heifetz A, Mohanty P, Fichman M, Sharadendu A, Nudelman R, Kauffman M, Noiman S.

Reference

Journal : J. Med. Chem.

Title : Physical binding pocket induction for affinity prediction.

PubMed ID : 19754201

DOI : 10.1021/jm901096y

Year : 2009

Volume : 52

Issue : 19

First Page : 6107

Last Page : 6125

Authors : Langham JJ, Cleves AE, Spitzer R, Kirshner D, Jain AN.

Abstract : Computational methods for predicting ligand affinity where no protein structure is known generally take the form of regression analysis based on molecular features that have only a tangential relationship to a protein/ligand binding event. Such methods have limited utility when structural variation moves beyond congeneric series. We present a novel approach based on the multiple-instance learning method of Compass, where a physical model of a binding site is induced from ligands and their corresponding activity data. The model consists of molecular fragments that can account for multiple positions of literal protein residues. We demonstrate the method on 5HT1a ligands by training on a series with limited scaffold variation and testing on numerous ligands with variant scaffolds. Predictive error was between 0.5 and 1.0 log units (0.7-1.4 kcal/mol), with statistically significant rank correlations. Accurate activity predictions of novel ligands were demonstrated using a validation approach where a small number of ligands of limited structural variation known at a fixed time point were used to make predictions on a blind test set of widely varying molecules, some discovered at a much later time point.

Reference

Journal : J Med Chem

Title : Natural-Products-Inspired Use of the gem-Dimethyl Group in Medicinal Chemistry.

PubMed ID : 28850227

DOI : 10.1021/acs.jmedchem.7b00315

Year : 2018

Volume : 61

Issue : 6

First Page : 2166

Last Page : 2210

Authors : Talele TT.

Abstract : The gem-dimethyl moiety is a structural feature frequently found in many natural products of clinical interest, including, but not limited to, taxanes, epothilones, statins, retinoids, di-/triterpenes, noviose deoxysugar, and antibiotics derived from β-lactams, macrolides, and aminocoumarins. Inspired by this time-tested moiety, medicinal chemists have widely explored its use in developing bioactive molecules because of the possibility to (1) increase target engagement, potency, and selectivity through van der Waals interactions and entropically favorable restriction to a bioactive conformation, (2) mitigate toxicity, (3) obtain superior DMPK profile, (4) modulate the p Ka of nearby functionality, (5) induce symmetry into a monomethyl substituted chiral center, and (6) apply the Thorpe-Ingold conformational effect in an o-hydroxydihydrocinnamic acid based prodrug design. The aim of this Perspective is to illustrate how medicinal chemists have elegantly employed the gem-dimethyl group to obtain clinically useful drugs and to provide synthetic methods to install a gem-dimethyl group.

Assay Description	Organism	Bioactivity
In vitro binding affinity against 5-hydroxytryptamine 1A receptor using [3H]8-OH-DPAT in human CYP3A4 assay	None	114.0 nM
In vitro ability to displace [3H]8-hydroxy-2-(di-n-propylamino) tetralin binding from 5-hydroxytryptamine 1A receptor site in rat brain hippocampus	None	31.8 nM
Evaluated for binding affinity towards 5-hydroxytryptamine 1A receptor in rat brain	None	70.0 nM
Displacement of [3H]8-OH-DPAT from human 5HT1A receptor in HEK293 cells	Homo sapiens	13.0 nM
Binding affinity to D2 receptor by radioligand binding assay	Homo sapiens	58.0 nM
Activity against 5HT1A receptor by Gi-[35S]GTP-gamma-S binding assay	Homo sapiens	288.0 nM
Binding affinity to 5HT1A receptor	None	79.43 nM
Binding affinity to 5-HT1A (unknown origin)	Homo sapiens	31.8 nM

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Cross References

Resources	Reference
ChEBI	135990
ChEMBL	CHEMBL284092
DrugBank	DB12184
DrugCentral	4562
FDA SRS	JW5Y7B8Z18
PubChem	55191
SureChEMBL	SCHEMBL79040
ZINC	ZINC000002021499

CONTENTS

Structure
Chemical and Physical Properties
Related Entries