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Negative modulators of metabotropic glutamate 2 & 3 receptors demonstrate antidepressant-like activity in animal models and hold promise as novel therapeutic agents for the treatment ...of major depressive disorder. Herein we describe our efforts to prepare and optimize a series of conformationally constrained 3,4-disubstituted bicyclo3.1.0hexane glutamic acid analogs as orthosteric (glutamate site) mGlu2/3 receptor antagonists. This work led to the discovery of a highly potent and efficacious tool compound 18 (hmGlu2 IC50 46±14.2nM, hmGlu3 IC50=46.1±36.2nM). Compound 18 showed activity in the mouse forced swim test with a minimal effective dose (MED) of 1mg/kg ip. While in rat EEG studies it exhibited wake promoting effects at 3 and 10mg/kg ip without any significant effects on locomotor activity. Compound 18 thus represents a novel tool molecule for studying the impact of blocking mGlu2/3 receptors both in vitro and in vivo.
Azetidinones as vasopressin V1a antagonists Guillon, Christophe D.; Koppel, Gary A.; Brownstein, Michael J. ...
Bioorganic & medicinal chemistry,
03/2007, Letnik:
15, Številka:
5
Journal Article
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The azetidinone LY307174 (
1) was identified as a screening lead for the vasopressin V1a receptor (IC
50 45
nM at the human V1a receptor) based on molecular similarity to ketoconazole (
2), a known ...antagonist of the luteinizing hormone releasing hormone receptor. Structure–activity relationships for the series were explored to optimize receptor affinity and pharmacokinetic properties, resulting in compounds with
K
i values <1
nM and brain levels after oral dosing ∼100-fold higher than receptor affinities.
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An 800 compound hydantoin library has been constructed using a diverse set of 20 amino acids and over 80 primary amines. Amino acids were attached via their N-termini to hydroxymethyl polystyrene ...using a carbamate linker. Bound amino acids were converted to their corresponding amides and then cyclized under basic conditions to give hydantoins in high purities.
Amino acids bound to hydroxymethyl polystyrene via their N-termini with a carbamate linker were converted to their corresponding amides and then cyclized under basic conditions to give hydantoins in high purities.
Solid supported nucleophiles and electrophiles are employed to expedite the work-up and purification of a variety of amine alkylations acylacylations. These solid suported scavengers are particularly ...advantageous for the construction of non-peptide libraries in a parallel array format.
Solid supported nucleophiles and electrophiles are useful for the rapid purification of a variety of solution phase reactions. Multi-step sequences are also conducted using this methodology which afford products in high purity.
A novel series of selective negative allosteric modulators (NAMs) for metabotropic glutamate receptor 5 (mGlu5) was discovered from an isothiazole scaffold. One compound of this series, ...(1R,2R)-N-(4-(6-isopropylpyridin-2-yl)-3-(2-methyl-2H-indazol-5-yl)isothiazol-5-yl)-2-methylcyclopropanecarboxamide (24), demonstrated satisfactory pharmacokinetic properties and, following oral dosing in rats, produced dose-dependent and long-lasting mGlu5 receptor occupancy. Consistent with the hypothesis that blockade of mGlu5 receptors will produce analgesic effects in mammals, compound 24 produced a dose-dependent reduction in paw licking responses in the formalin model of persistent pain.
Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 (3) ...as a novel, potent, and subtype selective human D1 positive allosteric modulator (PAM) with minimal allosteric agonist activity. Conformational studies showed LY3154207 adopts an unusual boat conformation, and a binding pose with the human D1 receptor was proposed based on this observation. In contrast to orthosteric agonists, LY3154207 showed a distinct pharmacological profile without a bell-shaped dose-response relationship or tachyphylaxis in preclinical models. Identification of a crystalline form of free LY3154207 from the discovery lots was not successful. Instead, a novel cocrystal form with superior solubility was discovered and determined to be suitable for development. This cocrystal form was advanced to clinical development as a potential first-in-class D1 PAM and is now in phase 2 studies for Lewy body dementia.
As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu2/3) receptors, we have incorporated substitution at the C3 and C4 positions of the ...(1S,2R,5R,6R)-2-amino-bicyclo3.1.0hexane-2,6-dicarboxylic acid scaffold to generate mGlu2/3 antagonists. Exploration of this structure–activity relationship (SAR) led to the identification of (1S,2R,3S,4S,5R,6R)-2-amino-3-(3,4-difluorophenyl)sulfanylmethyl-4-hydroxy-bicyclo3.1.0hexane-2,6-dicarboxylic acid hydrochloride (LY3020371·HCl, 19f), a potent, selective, and maximally efficacious mGlu2/3 antagonist. Further characterization of compound 19f binding to the human metabotropic 2 glutamate (hmGlu2) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu2 receptor protein. The resulting cocrystal structure revealed the specific ligand–protein interactions, which likely explain the high affinity of 19f for this site and support its functional mGlu2 antagonist pharmacology. Further characterization of 19f in vivo demonstrated an antidepressant-like signature in the mouse forced-swim test (mFST) assay when brain levels of this compound exceeded the cellular mGlu2 IC50 value.
A method for the solid phase synthesis of urea libraries from primary and secondary amines is described which utilizes a thiophenoxy carbonyl linker. Sequential release of different urea products ...from a common batch of resin using a “milking” procedure has also been accomplished.
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Using a combination of iterative structure-based design and an analysis of oral pharmacokinetics and antiviral activity, AG1343 (Viracept, nelfinavir mesylate), a nonpeptidic inhibitor of HIV-1 ...protease, was identified. AG1343 is a potent enzyme inhibitor (K i = 2 nM) and antiviral agent (HIV-1 ED50 = 14 nM). An X-ray cocrystal structure of the enzyme−AG1343 complex reveals how the novel thiophenyl ether and phenol−amide substituents of the inhibitor interact with the S1 and S2 subsites of HIV-1 protease, respectively. In vivo studies indicate that AG1343 is well absorbed orally in a variety of species and possesses favorable pharmacokinetic properties in humans. AG1343 (Viracept) has recently been approved for marketing for the treatment of AIDS.
Amines and acylated amines are synthesized in traditional solution phase reactions, then rapidly purified by ion exchange chromatography to yield pure products. In some instances, impurities devoid ...of ionizable functionality can be covalently modified prior to purification. The generic purification sequence is applicable to a variety of reactions, and is amenable to automation with commercially available equipment.
Ion exchange chromatography is employed for the purification of reactions yielding alkylated and acylated amines. This purification method can be readily automated to purify libraries of amine-containing compounds.
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