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1.
Bioorg Med Chem Lett ; 29(13): 1601-1604, 2019 07 01.
Article in English | MEDLINE | ID: mdl-31072652

ABSTRACT

This letter describes a focused, multi-dimensional optimization campaign around BL-1249, a fenamate class non-steroidal anti-inflammatory and a known activator of the K2P potassium channels TREK-1 (K2P2.1) and TREK-2 (K2P10.1). While BL-1249 has been widely profiled in vitro as a dual TREK-1/2 activator, poor physicochemical and DMPK properties have precluded a deeper understanding of the therapeutic potential of these key K2P channels across a broad spectrum of peripheral and central human disease. Here, we report multi-dimensional SAR that led to a novel TREK-1/2 dual activator chemotype, exemplified by ONO-2960632/VU6011992, with improved DMPK properties, representing a new lead for further optimization towards robust in vivo tool compounds.


Subject(s)
Potassium Channels, Tandem Pore Domain/metabolism , Tetrahydronaphthalenes/therapeutic use , Tetrazoles/therapeutic use , Humans , Tetrahydronaphthalenes/pharmacology , Tetrazoles/pharmacology
2.
J Med Chem ; 62(1): 378-384, 2019 01 10.
Article in English | MEDLINE | ID: mdl-30350962

ABSTRACT

A scaffold hopping exercise from a monocyclic mGlu2 NAM with poor rodent PK led to two novel heterobicyclic series of mGlu2 NAMs based on either a functionalized pyrazolo[1,5- a]pyrimidine-5-carboxamide core or a thieno[3,2- b]pyridine-5-carboxamide core. These novel analogues possess enhanced rodent PK, while also maintaining good mGlu2 NAM potency, selectivity (versus mGlu3 and the remaining six mGlu receptors), and high CNS penetration. Interestingly, SAR was divergent between the new 5,6-heterobicyclic systems.


Subject(s)
Amides/chemistry , Central Nervous System/metabolism , Receptors, Metabotropic Glutamate/chemistry , Allosteric Regulation , Amides/metabolism , Amides/pharmacokinetics , Animals , Drug Evaluation, Preclinical , Half-Life , Humans , Inhibitory Concentration 50 , Protein Isoforms/chemistry , Protein Isoforms/metabolism , Pyrazoles/chemistry , Pyridines/chemistry , Pyrimidines/chemistry , Rats , Receptors, Metabotropic Glutamate/metabolism , Structure-Activity Relationship
3.
Bioorg Med Chem Lett ; 29(2): 342-346, 2019 01 15.
Article in English | MEDLINE | ID: mdl-30503632

ABSTRACT

This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).


Subject(s)
Drug Discovery , Heterocyclic Compounds, 2-Ring/pharmacology , Isoquinolines/pharmacology , Myotonin-Protein Kinase/antagonists & inhibitors , Receptors, Metabotropic Glutamate/metabolism , Allosteric Regulation/drug effects , Dose-Response Relationship, Drug , Heterocyclic Compounds, 2-Ring/chemistry , Humans , Isoquinolines/chemistry , Molecular Structure , Myotonin-Protein Kinase/metabolism , Structure-Activity Relationship
4.
ACS Chem Neurosci ; 8(9): 1873-1879, 2017 09 20.
Article in English | MEDLINE | ID: mdl-28697302

ABSTRACT

The G protein-gated inwardly-rectifying potassium channels (GIRK, Kir3) are a family of inward-rectifying potassium channels, and there is significant evidence supporting the roles of GIRKs in a number of physiological processes and as potential targets for numerous indications. Previously reported urea containing molecules as GIRK1/2 preferring activators have had significant pharmacokinetic (PK) liabilities. Here we report a novel series of 1H-pyrazolo-5-yl-2-phenylacetamides in an effort to improve upon the PK properties. This series of compounds display nanomolar potency as GIRK1/2 activators with improved brain distribution (rodent Kp > 0.6).


Subject(s)
Acetamides/pharmacology , Acetamides/pharmacokinetics , G Protein-Coupled Inwardly-Rectifying Potassium Channels/metabolism , Membrane Transport Modulators/pharmacology , Membrane Transport Modulators/pharmacokinetics , Pyrazoles/pharmacology , Pyrazoles/pharmacokinetics , Animals , Brain/drug effects , Brain/metabolism , HEK293 Cells , Humans , Liver/drug effects , Liver/metabolism , Mice , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Molecular Structure , Structure-Activity Relationship
5.
Org Lett ; 18(15): 3766-9, 2016 08 05.
Article in English | MEDLINE | ID: mdl-27453257

ABSTRACT

Promising levels of enantiocontrol are observed in the silanediol-catalyzed addition of silyl ketene acetals to benzopyrylium triflates. This rare example of enantioselective, intermolecular chromenone functionalization with carbonyl-containing nucleophiles has potential applications in the synthesis of bioactive chromanones and tetrahydroxanthones.

6.
Org Lett ; 18(12): 2883-5, 2016 06 17.
Article in English | MEDLINE | ID: mdl-27255675

ABSTRACT

Sterically encumbered organosilanes can be difficult to synthesize with conventional, strongly basic reagents; the harsh reaction conditions are often low yielding and not suitable for many functional groups. As an alternative to the typical anionic strategies to construct silanes, the coupling of benzylic halides and arylhalosilanes with sonication has been identified as a high yielding and general strategy to access bulky and functionalized benzylic silanes. This new methodology provides a solution for the synthesis of families of bulky benzylic silanes for study in catalysis and other areas of chemical synthesis.

7.
Angew Chem Int Ed Engl ; 52(43): 11321-4, 2013 Oct 18.
Article in English | MEDLINE | ID: mdl-24039105

ABSTRACT

A perfect pair: Silanediols are effective catalysts for the addition of silyl ketene acetals to N-acylisoquinolinium ions. Importantly, this is the first example of a silanediol plausibly participating in anion-binding catalysis, a relatively new direction in the field of hydrogen-bond-donor catalysis. The chiral, enantiopure C2 -symmetric silanediol 1 catalyzes enantioselective transformations.

8.
J Org Chem ; 77(5): 2571-7, 2012 Mar 02.
Article in English | MEDLINE | ID: mdl-22296310

ABSTRACT

The effective conjugation of ortho and ortho-alt-para-arylene ethynylenes, with appropriately positioned pyridine and pyrazine heterocycles, increases upon binding to Ag(I) and Pd(II) cations. Significant bathochromic shifts in the electronic spectra, witnessed upon introduction of these metal bridges, are consistent with enhanced electron delocalization in the unsaturated backbone. Control studies suggest that this electronic behavior is attributable exclusively (in the case of Ag(I)) or partially (in the case of Pd(II)) to conformational restrictions of the conjugated backbones.


Subject(s)
Alkynes/chemistry , Organometallic Compounds/chemical synthesis , Palladium/chemistry , Silver/chemistry , Molecular Structure , Organometallic Compounds/chemistry , Pyrazines/chemistry , Pyridines/chemistry
9.
Org Lett ; 13(19): 5228-31, 2011 Oct 07.
Article in English | MEDLINE | ID: mdl-21894881

ABSTRACT

Silanediols are introduced as a new class of hydrogen bond donor catalysts for the activation of nitroalkenes toward nucleophilic attack. Excellent yields of product are obtained for the conjugate addition of indole to ß-nitrostyrene catalyzed with a stable, storable dinaphthyl-derived silanediol. The preparation and structural characterization of a C(2)-symmetric chiral silanediol is also reported along with its ability to catalyze the conjugate addition reaction.

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