Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

Felts, Andrew S.; Rodriguez, Alice L.; Morrison, Ryan D.; Blobaum, Anna L.; Byers, Frank W.; Daniels, J. Scott; Niswender, Colleen M.; Conn, P. Jeffrey; Lindsley, Craig W.; Emmitte, Kyle A.

doi:10.1016/j.bmcl.2018.04.053

Cited by 3 publications

References 21 publications

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The Design and Application of Bioisosteres in Drug Design

Meanwell

2021

Burger's Medicinal Chemistry and Drug Discovery

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Bioisosterism, the design of structural motifs that emulate established functionality to effect a biological response, has evolved into a powerful design principle in medicinal chemistry and drug discovery that can be implemented to address issues associated with intrinsic potency and/or a range of developability challenges. While bioisosterism has its origins in the concept of isosterism, which was invoked to explain the similarity of physicochemical properties between molecules with analogous size and shape, the contemporary interpretation of bioisosterism extends well beyond this simple definition to encompass relationships that reflect a recapitulation of biological properties by molecules that can be structurally quite disparate. This article provides a synopsis of established and emerging bioisosteric relationships that are discussed in the context of applications to solving problems in drug discovery and development. Bioisosteres that are described range from the replacement of hydrogen atoms by deuterium or fluorine to more esoteric higher order bioisosteres that convene intricate arrays of functionality. These are considered nonclassical in nature and offer functional mimesis of a range of simple and complex functionalities encompassing exchangeable groups, cyclic/noncyclic substructures capable of mimicking rings, and extends to include drug–water and drug–metal complexes.

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The Design and Application of Bioisosteres in Drug Design

Meanwell

2021

Burger's Medicinal Chemistry and Drug Discovery

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(Het)aryl Difluoromethyl‐Substituted β‐Alkoxyenones: Synthesis and Heterocyclizations

et al. 2020

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An efficient approach to the preparation of β‐alkoxyenones bearing (het)aryl difluoromethyl substituents is described. The method included acylation of acyclic or cyclic vinyl ethers with (het)aryl difluoroacetyl chlorides. The method worked well for most substrates, except aryl‐substituted derivatives bearing electron‐donating groups in o‐ or p‐positions, and heteroaromatic compounds bearing sufficiently basic nitrogen atom. Synthetic utility of (het)aryl difluoromethyl‐substituted β‐alkoxyenones as CCC bis‐electrophiles was demonstrated by heterocyclizations with common 1,2‐ and 1,3‐bis‐nucleophiles leading to compounds with (het)aryl–CF2–(het)aryl motif, in particular (het)aryl difluoromethyl‐substituted pyrazoles, isoxazoles, and pyrimidines – promising chemotypes for drug discovery.

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Recent Advancements in the Synthesis of α-fluoroalkylated Azine-derived Heterocycles through Direct Fluorination

Shavrina,

Rassukana,

Onysko

2024

COS

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Abstract:: The review highlights recent advancements in the synthesis of α-fluoro and α,α- difluoroalkylated azines, focusing on two main approaches. The first approach involves nucleophilic deoxofluorination, wherein α-hydroxy- or α-oxoalkylated azines are treated with diethylaminosulfur trifluoride or other S-F reagents to introduce fluorine atoms. The second approach employs direct electrophilic benzylic fluorination, whereby alkylazines undergo fluorination using N-F reagents. Both methods provide flexibility in designing and synthesizing fluoroalkylated heterocycles.

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Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

Cited by 3 publications

References 21 publications

The Design and Application of Bioisosteres in Drug Design

The Design and Application of Bioisosteres in Drug Design

(Het)aryl Difluoromethyl‐Substituted β‐Alkoxyenones: Synthesis and Heterocyclizations

Recent Advancements in the Synthesis of α-fluoroalkylated Azine-derived Heterocycles through Direct Fluorination

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