11 research outputs found
Macrocyclic Drugs and Clinical Candidates: What Can Medicinal Chemists Learn from Their Properties?
Macrocycles
are ideal in efforts to tackle âdifficultâ
targets, but our understanding of what makes them cell permeable and
orally bioavailable is limited. Analysis of approximately 100 macrocyclic
drugs and clinical candidates revealed that macrocycles are predominantly
used for infectious disease and in oncology and that most belong to
the macrolide or cyclic peptide class. A significant number (<i>N</i> = 34) of these macrocycles are administered orally, revealing
that oral bioavailability can be obtained at molecular weights up
to and above 1 kDa and polar surface areas ranging toward 250 Ă
<sup>2</sup>. Moreover, insight from a group of âde novo designedâ
oral macrocycles in clinical studies and understanding of how cyclosporin
A and model cyclic hexapeptides cross cell membranes may unlock wider
opportunities in drug discovery. However, the number of oral macrocycles
is still low and it remains to be seen if they are outliers or if
macrocycles will open up novel oral druggable space
Intramolecular Hydrogen Bond Expectations in Medicinal Chemistry
Design strategies centered on intramolecular
hydrogen bonds are sometime used in drug discovery, but their general
applicability has not been addressed beyond scattered examples or
circumstantial evidence. A total of 1053 matched molecular pairs where
only one of the two molecules is able to form an intramolecular hydrogen
bond via monatomic transformations have been identified across the
ChEMBL database. These pairs were used to investigate the effect of
intramolecular hydrogen bonds on biological activity. While cases
of extreme, conflicting variation of effect emerge, the mean biological
activity difference for a pair is close to zero and does not exceed
±0.5
log biological activity for over 50% of the analyzed sample
Exploiting Structural Information in Patent Specifications for Key Compound Prediction
Patent specifications are one of many information sources
needed
to progress drug discovery projects. Understanding compound prior
art and novelty checking, validation of biological assays, and identification
of new starting points for chemical explorations are a few areas where
patent analysis is an important component. Cheminformatics methods
can be used to facilitate the identification of so-called key compounds
in patent specifications. Such methods, relying on structural information
extracted from documents by expert curation or text mining, can complement
or in some cases replace the traditional manual approach of searching
for clues in the text. This paper describes and compares three different
methods for the automatic prediction of key compounds in patent specifications
using structural information alone. For this data set, the cluster
seed analysis described by Hattori et al. (Hattori, K.; Wakabayashi,
H.; Tamaki, K. Predicting key example compounds in competitors' patent
applications using structural information alone. <i>J. Chem.
Inf. Model.</i> <b>2008</b>, <i>48</i>, 135â142)
is superior in terms of prediction accuracy with 26 out of 48 drugs
(54%) correctly predicted from their corresponding patents. Nevertheless,
the two new methods, based on frequency of R-groups (FOG) and maximum
common substructure (MCS) similarity measures, show significant advantages
due to their inherent ability to visualize relevant structural features.
The results of the FOG method can be enhanced by manual selection
of the scaffolds used in the analysis. Finally, a successful example
of applying FOG analysis for designing potent ATP-competitive AXL
kinase inhibitors with improved properties is described
Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC<sub>2</sub> Agonism and Glucose-Dependent Insulin Secretion
Agonists
of vasoactive intestinal peptide receptor 2 (VPAC<sub>2</sub>) stimulate
glucose-dependent insulin secretion, making them attractive candidates
for the treatment of hyperglycaemia and type-II diabetes. Vasoactive
intestinal peptide (VIP) is an endogenous peptide hormone that potently
agonizes VPAC<sub>2</sub>. However, VIP has a short serum half-life
and poor pharmacokinetics in vivo and is susceptible to proteolytic
degradation, making its development as a therapeutic agent challenging.
Here, we investigated two peptide cyclization strategies, lactamisation
and olefin-metathesis stapling, and their effects on VPAC<sub>2</sub> agonism, peptide secondary structure, protease stability, and cell
membrane permeability. VIP analogues showing significantly enhanced
VPAC<sub>2</sub> agonist potency, glucose-dependent insulin secretion
activity, and increased helical content were discovered; however,
neither cyclization strategy appeared to effect proteolytic stability
or cell permeability of the resulting peptides
Design and Synthesis of Fsp<sup>3</sup>âRich, Bis-Spirocyclic-Based Compound Libraries for Biological Screening
The
exploration of innovative chemical space is a critical step
in the early phases of drug discovery. Bis-spirocyclic frameworks
occur in natural products and other biologically relevant metabolites
and show attractive features, such as molecular compactness, structural
complexity, and three-dimensional character. A concise approach to
the synthesis of bis-spirocyclic-based compound libraries starting
from readily available commercial reagents and robust chemical transformations
has been developed. A number of novel bis-spirocyclic scaffold examples,
as implemented in the European Lead Factory project, is presented
Inhibitors to Overcome Secondary Mutations in the Stem Cell Factor Receptor KIT
In modern cancer therapy, the use
of small organic molecules against
receptor tyrosine kinases (RTKs) has been shown to be a valuable strategy.
The association of cancer cells with dysregulated signaling pathways
linked to RTKs represents a key element in targeted cancer therapies.
The tyrosine kinase mast/stem cell growth factor receptor KIT is an
example of a clinically relevant RTK. KIT is targeted for cancer therapy
in gastrointestinal stromal tumors (GISTs) and chronic myelogenous
leukemia (CML). However, acquired resistance mutations within the
catalytic domain decrease the efficacy of this strategy and are the
most common cause of failed therapy. Here, we present the structure-based
design and synthesis of novel type II kinase inhibitors to overcome
these mutations in KIT. Biochemical and cellular studies revealed
promising molecules for the inhibition of mutated KIT
Lead Optimization of Ethyl 6âAminonicotinate Acyl Sulfonamides as Antagonists of the P2Y<sub>12</sub> Receptor. Separation of the Antithrombotic Effect and Bleeding for Candidate Drug AZD1283
Synthesis and structureâactivity
relationships of ethyl
6-aminonicotinate acyl sulfonamides, which are potent antagonists
of the P2Y<sub>12</sub> receptor, are presented. Shifting from 5-chlorothienyl
to benzyl sulfonamides significantly increased the potency in the
residual platelet count assay. Evaluation of PK parameters in vivo
in dog for six compounds showed a 10-fold higher clearance for the
azetidines than for the matched-pair piperidines. In a modified Folts
model in dog, both piperidine <b>3</b> and azetidine <b>13</b> dose-dependently induced increases in blood flow and inhibition
of ADP-induced platelet aggregation with antithrombotic ED<sub>50</sub> values of 3.0 and 10 ÎŒg/kg/min, respectively. The doses that
induced a larger than 3-fold increase in bleeding time were 33 and
100 ÎŒg/kg/min for <b>3</b> and <b>13</b>, respectively.
Thus, the therapeutic index (TI) was â„10 for both compounds.
On the basis of these data, compound <b>3</b> was progressed
into human clinical trials as candidate drug AZD1283
Discovery of AZD2716: A Novel Secreted Phospholipase A<sub>2</sub> (sPLA<sub>2</sub>) Inhibitor for the Treatment of Coronary Artery Disease
Expedited
structure-based optimization of the initial fragment hit <b>1</b> led to the design of (<i>R</i>)-<b>7</b> (AZD2716)
a novel, potent secreted phospholipase A<sub>2</sub> (sPLA<sub>2</sub>) inhibitor with excellent preclinical pharmacokinetic properties
across species, clear <i>in vivo</i> efficacy, and minimized
safety risk. Based on accumulated profiling data, (<i>R</i>)-<b>7</b> was selected as a clinical candidate for the treatment
of coronary artery disease
Impact of Stereospecific Intramolecular Hydrogen Bonding on Cell Permeability and Physicochemical Properties
Profiling
of eight stereoisomeric <i>T. cruzi</i> growth
inhibitors revealed vastly different in vitro properties such as solubility,
lipophilicity, p<i>K</i><sub>a</sub>, and cell permeability
for two sets of four stereoisomers. Using computational chemistry
and NMR spectroscopy, we identified the formation of an intramolecular
NHâNR<sub>3</sub> hydrogen bond in the set of stereoisomers
displaying lower solubility, higher lipophilicity, and higher cell
permeability. The intramolecular hydrogen bond resulted in a significant
p<i>K</i><sub>a</sub> difference that accounts for the other
structureâproperty relationships. Application of this knowledge
could be of particular value to maintain the delicate balance of size,
solubility, and lipophilicity required for cell penetration and oral
administration for chemical probes or therapeutics with properties
at, or beyond, Lipinskiâs rule of 5
Design of Selective sPLA<sub>2</sub>âX Inhibitor (â)-2-{2-[Carbamoyl-6-(trifluoromethoxy)â1<i>H</i>âindol-1-yl]pyridine-2-yl}propanoic Acid
A lead
generation campaign identified indole-based sPLA<sub>2</sub>-X inhibitors
with a promising selectivity profile against other
sPLA<sub>2</sub> isoforms. Further optimization of sPLA<sub>2</sub> selectivity and metabolic stability resulted in the design of (â)-<b>17</b>, a novel, potent, and selective sPLA<sub>2</sub>-X inhibitor
with an exquisite pharmacokinetic profile characterized by high absorption
and low clearance, and low toxicological risk. Compound (â)-<b>17</b> was tested in an ApoE<sup>â/â</sup> murine
model of atherosclerosis to evaluate the effect of reversible, pharmacological
sPLA<sub>2</sub>-X inhibition on atherosclerosis development. Despite
being well tolerated and achieving adequate systemic exposure of mechanistic
relevance, (â)-<b>17</b> did not significantly affect
circulating lipid and lipoprotein biomarkers and had no effect on
coronary function or histological markers of atherosclerosis