29 research outputs found
Demonstration of the innate electrophilicity of 4-(3-(benzyloxy)phenyl)-2-(ethylsulfinyl)-6trifluoromethyl)pyrimidine (BETP), a small molecule positive allosteric modulator of the glucagon-like peptide-1. Drug Metab. Dispos
ABSTRACT 4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP) represents a novel small-molecule activator of the glucagonlike peptide-1 receptor (GLP-1R), and exhibits glucose-dependent insulin secretion in rats following i.v. (but not oral) administration. To explore the quantitative pharmacology associated with GLP-1R agonism in preclinical species, the in vivo pharmacokinetics of BETP were examined in rats after i.v. and oral dosing. Failure to detect BETP in circulation after oral administration of a 10-mg/kg dose in rats was consistent with the lack of an insulinotropic effect of orally administered BETP in this species. Likewise, systemic concentrations of BETP in the rat upon i.v. administration (1 mg/kg) were minimal (and sporadic). In vitro incubations in bovine serum albumin, plasma, and liver microsomes from rodents and humans indicated a facile degradation of BETP. Failure to detect metabolites in plasma and liver microsomal incubations in the absence of NADP was suggestive of a covalent interaction between BETP and a protein amino acid residue(s) in these matrices. Incubations of BETP with glutathione (GSH) in buffer revealed a rapid nucleophilic displacement of the ethylsulfoxide functionality by GSH to yield adduct M1, which indicated that BETP was intrinsically electrophilic. The structure of M1 was unambiguously identified by comparison of its chromatographic and mass spectral properties with an authentic standard. The GSH conjugate of BETP was also characterized in NADPH-and GSH-supplemented liver microsomes and in plasma samples from the pharmacokinetic studies. Unlike BETP, M1 was inactive as an allosteric modulator of the GLP-1R
Synthesis of a beta-lactam and enantiomeric resolution as the undecenyl ester derivative
Thesis (B.S.) in Chemistry -- University of Illinois at Urbana-Champaign, 1991.Includes bibliographical references (leaves 38-39)Microfiche of typescript. [Urbana, Ill.]: Photographic Services, University of Illinois, U of I Library, [1991]. 2 microfiches (46 frames): negative.s 1991 ilu n
A New and Useful Method for the Macrocyclization of Linear Peptides
A new and useful procedure for the macrocyclization of linear peptides is described. The natural amino acid side chains of tyrosine (phenol), lysine (alkylamine), and histidine (imidazole) react in an intramolecular fashion with a pendent pyridine-<i>N</i>-oxide-carboxamide, which is selectively activated by the phosphonium salt, PyBroP. The reaction is mild, rapid, and efficient with a potentially large substrate scope. Multiple examples are provided with full characterization and analyses, including a novel aza-variant of the C–O–D ring system of vancomycin
Convergent Syntheses of Isomeric Imidazolospiroketones as Templates for Acetyl-CoA Carboxylase (ACC) Inhibitors
The synthesis of imidazole fused spirocyclic ketones
as templates
for acetyl-CoA carboxylase (ACC) inhibitors is reported. By completing
the spirocyclic ring closure via divergent pathways, the synthesis
of these regioisomers from common intermediates was developed. Through
an aldehyde homologation/transmetalation strategy, one isomer was
formed selectively. The second desired isomer was obtained via an
intramolecular aromatic homolytic substitution reaction. Preparation
of these isomeric spiroketones provided templates which, upon elaboration,
led to key structure–activity relationship (SAR) points for
delivery of potent ACC inhibitors
Macrocyclizations for Medicinal Chemistry: Synthesis of Druglike Macrocycles by High-Concentration Ullmann Coupling
Conditions have been identified for the efficient Ullmann
macrocyclization
of phenol and imidazole nucleophiles with aryl iodides at high reaction
concentrations of up to 100 mM and using 5–10 mol % loading
of an inexpensive copper catalyst. A range of substitution patterns
and ring sizes are tolerated, and the method has been exemplified
by the synthesis of a set of druglike macrocycles
In Vitro Metabolism of the Glucagon-Like Peptide-1 (GLP-1)–Derived Metabolites GLP-1(9-36)amide and GLP-1(28-36)amide in Mouse and Human Hepatocytes
Biaryl-Bridged Macrocyclic Peptides: Conformational Constraint via Carbogenic Fusion of Natural Amino Acid Side Chains
A general method for constraining peptide conformations
via linkage of aromatic sidechains has been developed. Macrocyclization
of suitably functionalized tri-, tetra- and pentapeptides via Suzuki–Miyaura
cross-coupling has been used to generate side chain to side chain,
biaryl-bridged 14- to 21-membered macrocyclic peptides. Biaryl bridges
possessing three different configurations, meta–meta, meta–ortho,
and ortho–meta, were systematically explored through regiochemical
variation of the aryl halide and aryl boronate coupling partners,
allowing fine-tuning of the resultant macrocycle conformation. Suzuki–Miyaura
macrocyclizations were successfully achieved both in solution and
on solid phase for all three sizes of peptide. This approach constitutes
a means of constraining peptide conformation via direct carbogenic
fusion of side chains of naturally occurring amino acids such as phenylalanine
and tyrosine, and so is complementary to strategies involving non-natural,
for example, hydrocarbon, bridges
Demonstration of the Innate Electrophilicity of 4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP), a Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor
Nonclassical Size Dependence of Permeation Defines Bounds for Passive Adsorption of Large Drug Molecules
Macrocyclic peptides are considered
large enough to inhibit “undruggable” targets, but the
design of passively cell-permeable molecules in this space remains
a challenge due to the poorly understood role of molecular size on
passive membrane permeability. Using split-pool combinatorial synthesis,
we constructed a library of cyclic, per-N-methlyated peptides spanning
a wide range of calculated lipohilicities (0 < <i>A</i>log<i>P</i> < 8) and molecular weights (∼800
Da < MW < ∼1200 Da). Analysis by the parallel artificial
membrane permeability assay revealed a steep drop-off in apparent
passive permeability with increasing size in stark disagreement with
current permeation models. This observation, corroborated by a set
of natural products, helps define criteria for achieving permeability
in larger molecular size regimes and suggests an operational cutoff,
beyond which passive permeability is constrained by a sharply increasing
penalty on membrane permeation