5 research outputs found
3D Molecular Descriptors Important for Clinical Success
The pharmacokinetic and safety profiles of clinical drug
candidates
are greatly influenced by their requisite physicochemical properties.
In particular, it has been shown that 2D molecular descriptors such
as fraction of Sp3 carbon atoms (Fsp3) and number of stereo centers
correlate with clinical success. Using
the proteomic off-target hit rate of nicotinic ligands, we found that
shape-based 3D descriptors such as the radius of gyration and shadow
indices discriminate off-target promiscuity better than do Fsp3 and
the number of stereo centers. We have deduced the relevant descriptor
values required for a ligand to be nonpromiscuous. Investigating the
MDL Drug Data Report (MDDR) database as compounds move from the preclinical
stage toward the market, we have found that these shape-based 3D descriptors
predict clinical success of compounds at preclinical and phase1 stages
vs compounds withdrawn from the market better than do Fsp3 and LogD.
Further, these computed 3D molecular descriptors correlate well with
experimentally observed solubility, which is among well-known physicochemical
properties that drive clinical success. We also found that about 84%
of launched drugs satisfy either Shadow index or Fsp3 criteria, whereas
withdrawn and discontinued compounds fail to meet the same criteria.
Our studies suggest that spherical compounds (rather than their elongated
counterparts) with a minimal number of aromatic rings may exhibit
a high propensity to advance from clinical trials to market
3D Molecular Descriptors Important for Clinical Success
The pharmacokinetic and safety profiles of clinical drug
candidates
are greatly influenced by their requisite physicochemical properties.
In particular, it has been shown that 2D molecular descriptors such
as fraction of Sp3 carbon atoms (Fsp3) and number of stereo centers
correlate with clinical success. Using
the proteomic off-target hit rate of nicotinic ligands, we found that
shape-based 3D descriptors such as the radius of gyration and shadow
indices discriminate off-target promiscuity better than do Fsp3 and
the number of stereo centers. We have deduced the relevant descriptor
values required for a ligand to be nonpromiscuous. Investigating the
MDL Drug Data Report (MDDR) database as compounds move from the preclinical
stage toward the market, we have found that these shape-based 3D descriptors
predict clinical success of compounds at preclinical and phase1 stages
vs compounds withdrawn from the market better than do Fsp3 and LogD.
Further, these computed 3D molecular descriptors correlate well with
experimentally observed solubility, which is among well-known physicochemical
properties that drive clinical success. We also found that about 84%
of launched drugs satisfy either Shadow index or Fsp3 criteria, whereas
withdrawn and discontinued compounds fail to meet the same criteria.
Our studies suggest that spherical compounds (rather than their elongated
counterparts) with a minimal number of aromatic rings may exhibit
a high propensity to advance from clinical trials to market
3D Molecular Descriptors Important for Clinical Success
The pharmacokinetic and safety profiles of clinical drug
candidates
are greatly influenced by their requisite physicochemical properties.
In particular, it has been shown that 2D molecular descriptors such
as fraction of Sp3 carbon atoms (Fsp3) and number of stereo centers
correlate with clinical success. Using
the proteomic off-target hit rate of nicotinic ligands, we found that
shape-based 3D descriptors such as the radius of gyration and shadow
indices discriminate off-target promiscuity better than do Fsp3 and
the number of stereo centers. We have deduced the relevant descriptor
values required for a ligand to be nonpromiscuous. Investigating the
MDL Drug Data Report (MDDR) database as compounds move from the preclinical
stage toward the market, we have found that these shape-based 3D descriptors
predict clinical success of compounds at preclinical and phase1 stages
vs compounds withdrawn from the market better than do Fsp3 and LogD.
Further, these computed 3D molecular descriptors correlate well with
experimentally observed solubility, which is among well-known physicochemical
properties that drive clinical success. We also found that about 84%
of launched drugs satisfy either Shadow index or Fsp3 criteria, whereas
withdrawn and discontinued compounds fail to meet the same criteria.
Our studies suggest that spherical compounds (rather than their elongated
counterparts) with a minimal number of aromatic rings may exhibit
a high propensity to advance from clinical trials to market
Discovery of (2<i>S</i>,3<i>R</i>)‑<i>N</i>‑[2-(Pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]benzo[<i>b</i>]furan-2-carboxamide (TC-5619), a Selective α7 Nicotinic Acetylcholine Receptor Agonist, for the Treatment of Cognitive Disorders
(2<i>S</i>,3<i>R</i>)-<i>N</i>-[2-(Pyridin-3-ylmethyl)-1-azabicycloÂ[2.2.2]Âoct-3-yl]ÂbenzoÂ[<i>b</i>]Âfuran-2-carboxamide (<b>7a</b>, TC-5619), a novel
selective agonist of the α7 neuronal nicotinic acetylcholine
receptor, has been identified as a promising drug candidate for the
treatment of cognitive impairment associated with neurological disorders. <b>7a</b> demonstrated more than a thousand-fold separation between
the affinities for the α7 and α4β2 receptor subtypes
and had no detectable effects on muscle or ganglionic nicotinic receptor
subtypes, indicating a marked selectivity for the central nervous
system over the peripheral nervous system. Results obtained from homology
modeling and docking explain the observed selectivity. <b>7a</b> had positive effects across cognitive, positive, and negative symptoms
of schizophrenia in animal models and was additive or synergistic
with the antipsychotic clozapine. Compound <b>7a</b>, as an
augmentation therapy to the standard treatment with antipsychotics,
demonstrated encouraging results on measures of negative symptoms
and cognitive dysfunction in schizophrenia and was well tolerated
in a phase II clinical proof of concept trial in patients with schizophrenia
Discovery of 3‑(5-Chloro-2-furoyl)-3,7-diazabicyclo[3.3.0]octane (TC-6683, AZD1446), a Novel Highly Selective α4β2 Nicotinic Acetylcholine Receptor Agonist for the Treatment of Cognitive Disorders
Diversification of essential nicotinic cholinergic pharmacophoric
elements, i.e., cationic center and hydrogen bond acceptor, resulted
in the discovery of novel potent α4β2 nAChR selective
agonists comprising a series of <i>N</i>-acyldiazabicycles.
Core characteristics of the series are an exocyclic carbonyl moiety
as a hydrogen bond acceptor and endocyclic secondary amino group.
These features are positioned at optimal distance and with optimal
relative spatial orientation to provide near optimal interactions
with the receptor. A novel potent and highly selective α4β2
nAChR agonist 3-(5-chloro-2-furoyl)-3,7-diazabicyclo[3.3.0]Âoctane
(<b>56</b>, TC-6683, AZD1446) with favorable pharmaceutical
properties and in vivo efficacy in animal models has been identified
as a potential treatment for cognitive deficits associated with psychiatric
or neurological conditions and is currently being progressed to phase
2 clinical trials as a treatment for Alzheimer’s disease