Browse
Submit Data
Databases
API
Help

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Pharmacophore-Based Design of Phenyl-[hydroxycyclohexyl] Cycloalkyl-Carboxamide Mitofusin Activators with Improved Neuronal Activity.

ABSTRACT: Mitochondrial fragmentation from defective fusion or unopposed fission contributes to many neurodegenerative diseases. Small molecule mitofusin activators reverse mitochondrial fragmentation in vitro, promising a novel therapeutic approach. The first-in-class mitofusin activator, 2, has a short plasma t_1/2 and limited neurological system bioavailability, conferring "burst activation". Here, pharmacophore-based rational redesign generated analogues of 2 incorporating cycloalkyl linker groups. A cyclopropyl-containing linker, 5, improved plasma and brain t_1/2, increased nervous system bioavailability, and prolonged neuron pharmacodynamic effects. Functional and single-crystal X-ray diffraction studies of stereoisomeric analogues of 5 containing sulfur as a "heavy atom", 14A and 14B, showed that 5 biological activity resides in the trans-R/R configuration, 5B. Structural analysis revealed stereoselective interactions of 5 associated with its mimicry of MFN2 Val372, Met376, and His380 side chains. Modification of murine ALS phenotypes in vitro and in vivo supports advancement of 5B for neurological conditions that may benefit from sustained mitofusin activation.

SUBMITTER: Dang X

PROVIDER: S-EPMC8632069 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

1-Benzoyl-N-phenyl-cyclo-propane-carboxamide.

Project description:The title compound, C(17)H(15)NO(2), was synthesized by reaction of 1,2-dibromo-ethane with 1-benzoyl-N-phenyl-cyclo-propane-carboxamide and K(2)CO(3) in dimethyl-formamide. The mol-ecule exhibits a V-shaped conformation in the crystal with a dihedral angle of 88.7 (3)° between the two benzene rings. Pairs of N-H⋯O hydrogen bonds link the mol-ecules into dimers about centres of inversion.

| S-EPMC2959514 | biostudies-literature

(S)-5-Oxo-N-phenyl-pyrrolidine-2-carboxamide.

Project description:The title compound, C(11)H(12)N(2)O(2), shows an S configuration, in which the pyrrolidinone ring is twisted with respect to the phenyl plane, making a dihedral angle of 70.73?(7)°. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds, building up a layer parallel to (001).

| S-EPMC3201468 | biostudies-literature

Design, synthesis and antifungal activity of threoninamide carbamate derivatives via pharmacophore model.

Project description:Thirty-six novel threoninamide carbamate derivatives were designed and synthesised using active fragment-based pharmacophore model. Antifungal activities of these compounds were tested against Oomycete fungi Phytophthora capsici in vitro and in vivo. Interestingly, compound I-1, I-2, I-3, I-6 and I-7 exhibited moderate control effect (>50%) against Pseudoperonospora cubensis in greenhouse at 6.25 μg/mL, which is better than that of control. Meanwhile most of these compounds exhibited significant inhibitory against P. capsici. The other nine fungi were also tested. More importantly, some compounds exhibited remarkably high activities against Sclerotinia sclerotiorum, P. piricola and R. solan in vitro with EC50 values of 3.74-9.76 μg/mL. It is possible that the model is reliabile and this method can be used to discover lead compounds for the development of fungicides.

| S-EPMC7144198 | biostudies-literature

N-Phenyl-morpholine-4-carboxamide.

Project description:In the title compound, C(11)H(14)N(2)O(2), the urea-type NC=ON moiety [planar to within 0.0002?(13)?Å] is inclined to the phenyl ring by 42.88?(8)?Å, and the morpholine ring has a chair conformation. In the crystal, inter-molecular N-H?O hydrogen bonds link the mol-ecules into infinite chains in [001].

| S-EPMC3050126 | biostudies-other

Fast GCaMPs for improved tracking of neuronal activity.

Project description:The use of genetically encodable calcium indicator proteins to monitor neuronal activity is hampered by slow response times and a narrow Ca(2+)-sensitive range. Here we identify three performance-limiting features of GCaMP3, a popular genetically encodable calcium indicator protein. First, we find that affinity is regulated by the calmodulin domain's Ca(2+)-chelating residues. Second, we find that off-responses to Ca(2+) are rate-limited by dissociation of the RS20 domain from calmodulin's hydrophobic pocket. Third, we find that on-responses are limited by fast binding to the N-lobe at high Ca(2+) and by slow binding to the C-lobe at lower Ca(2+). We develop Fast-GCaMPs, which have up to 20-fold accelerated off-responses and show that they have a 200-fold range of K(D), allowing coexpression of multiple variants to span an expanded range of Ca(2+) concentrations. Finally, we show that Fast-GCaMPs track natural song in Drosophila auditory neurons and generate rapid responses in mammalian neurons, supporting the utility of our approach.

| S-EPMC3824390 | biostudies-literature

N-Phenyl-2-(propan-2-yl-idene)-hydrazine-carboxamide.

Project description:In the title compound, C(10)H(13)N(3)O, the hydrazinecarboxamide N-N-C(=O)-N unit is nearly planar [maximum deviation = 0.018?(2)?Å] and is inclined at a dihedral angle of 8.45?(10)° with respect to the plane of the phenyl ring. The mol-ecular structure is stabilized by an intra-molecular C-H?O hydrogen bond which generates an S(6) ring motif. In the crystal, mol-ecules are linked into an inversion dimer by pairs of N-H?O and C-H?O hydrogen bonds.

| S-EPMC3295459 | biostudies-literature

3-(1-Naphth-yl)-N-phenyl-oxirane-2-carboxamide.

Project description:In the title compound, C(19)H(15)NO(2), the mol-ecule adopts a syn configuration with the naphthalene and N-phenyl-formamide units located on the same side of the ep-oxy ring. The ep-oxy ring makes dihedral angles of 58.73?(9) and 65.18?(9)°, respectively, with the naphthalene ring system and the benzene ring. Inter-molecular N-H?O and C-H?O hydrogen bonding is present in the crystal structure.

| S-EPMC2971758 | biostudies-literature

N-Isopropyl-6-methyl-2-phenyl-quinoline-3-carboxamide.

Project description:In the title compound, C(20)H(20)N(2)O, the dihedral angle between the quinoline ring system and the phenyl ring is 49.40 (5)°. In the crystal structure, zigzag layers of mol-ecules, in which the quinoline units are parallel to the (10) plane, are arranged perpendicular to the b axis. Inter-molecular N-H⋯O hydrogen bonds connect the mol-ecules into chains along [010], reinforcing the cohesion between the layers of the structure.

| S-EPMC3008085 | biostudies-literature

Discovery of 6-Phenylhexanamide Derivatives as Potent Stereoselective Mitofusin Activators for the Treatment of Mitochondrial Diseases.

Project description:Mutations in the mitochondrial fusion protein mitofusin (MFN) 2 cause the chronic neurodegenerative condition Charcot-Marie-Tooth disease type 2A (CMT2A), for which there is currently no treatment. Small-molecule activators of MFN1 and MFN2 enhance mitochondrial fusion and offer promise as therapy for this condition, but prototype compounds have poor pharmacokinetic properties. Herein, we describe a rational design of a series of 6-phenylhexanamide derivatives whose pharmacokinetic optimization yielded a 4-hydroxycyclohexyl analogue, 13, with the potency, selectivity, and oral bioavailability of a preclinical candidate. Studies of 13 cis- and trans-4-hydroxycyclohexyl isostereomers unexpectedly revealed functionality and protein engagement exclusively for the trans form, 13B. Preclinical absorption, distribution, metabolism, and excretion (ADME) and in vivo target engagement studies of 13B support further development of 6-phenylhexanamide derivatives as therapeutic agents for human CMT2A.

| S-EPMC7731667 | biostudies-literature

N-(Phenyl-sulfon-yl)naphtho-[2,1-b]furan-1-carboxamide.

Project description:In the title compound, C(19)H(13)NO(4)S, the mol-ecule is twisted at the S atom with a C-S-N-C torsion angle of -65.2?(2)° between the benzene ring and the -SO(2)-NH-C=O segment. The dihedral angle between the benzene and the naphtho-furan ring system is 83.3?(1)°. In the crystal, mol-ecules are linked by N-H?O hydrogen bonds into chains running along the c axis. An intra-molecular N-H?O(furan) inter-action is also observed.

| S-EPMC3239115 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data