Calcitonin gene-related peptide (CGRP) receptor antagonists: Pyridine as a replacement for a core amide group

Luo, Guanglin; Chen, Ling; Civiello, Rita L.; Pin, Sokhom S.; Xu, Cen; Kostich, Walter; Kelley, Michelle; Conway, Charles M.; Macor, John E.; Dubowchik, Gene M.

doi:10.1016/j.bmcl.2012.02.065

Cited by 20 publications

(22 citation statements)

References 16 publications

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“…It was noted that the pyridyl-ring nitrogen was 4.1 Å from the backbone NH of Leu312, a residue involved in binding histone H4 peptide. 13 Amino pyridine analogues have been used as bioisosteric replacements for amides 14 due to their ability to retain hydrogen bonding interactions or providing conformational restraint. Here, this bioisostere replacement strategy was reversed, aiming to increase the conformational flexibility of the H-bond acceptor and increasing the potential of gaining a hydrogen bond with Leu312.…”

mentioning

confidence: 99%

Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666

Duncan

Rioux

Boriack-Sjodin

et al. 2015

ACS Med. Chem. Lett.

116

108

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ABSTRACT:The recent publication of a potent and selective inhibitor of protein methyltransferase 5 (PRMT5) provides the scientific community with in vivo-active tool compound EPZ015666 (GSK3235025) to probe the underlying pharmacology of this key enzyme. Herein, we report the design and optimization strategies employed on an initial hit compound with poor in vitro clearance to yield in vivo tool compound EPZ015666 and an additional potent in vitro tool molecule EPZ015866 (GSK3203591). KEYWORDS:Methyltransferase, PRMT5, property based optimization, structure guided design T he mammalian protein arginine methyltransferases are a group of nine enzymes that perform N G -mono methylation-, asymmetric-, or symmetric dimethylation of arginine residues on a range of nuclear and cytoplasmic protein substrates.1 One member of this group, PRMT5, is capable of performing methylation of up to two methyl groups and is currently believed to be the predominant enzyme for symmetric dimethylation. PRMT5 may play an important role in tumorigenesis and is upregulated in several human malignancies.2−8 The mechanism behind the cell-transforming capabilities of PRMT5 has been postulated to have roles in cell death, cell-cycle progression and cell growth, and proliferation and is still under investigation.9 Whether PRMT5 drives tumorigenesis by direct signal transduction, regulating gene expression, or by some other mechanism is generally unknown, although recent studies highlight a dependency on PRMT5 as part of the spliceosomal machinery with Sm proteins, particularly for MYC-driven tumors. 10EPZ015666 has recently been characterized as a potent inhibitor and in vivo tool compound of PRMT5.11 This compound is the first inhibitor to be described with a well characterized correlation between inhibition of PRMT5 enzyme and reduction of known substrate products including symmetric-dimethylated SmD3, coupled with a corresponding effect on tumor growth inhibition. In addition, structural biology studies highlighted a unique cation−π binding mode involving the tetrahydroisoquinoline (THIQ) containing chemical series as exemplified in the EPZ015666:PRMT5:-MEP50 cocrystal complex (PDB Codes: 4X60, 4X61). Herein we describe the medicinal chemistry optimization (Figure 1) in the development of tool compound EPZ015666.Compound 1 was recently described 11 as a hit identified from a 370 K member diversity high throughput screening (HTS) campaign, with modest inhibitory activity against PRMT5. Scheme 1 shows the synthetic route employed for the optimization of 1, as it enabled identification of SAR around the THIQ group at the penultimate step. Retaining the cyclopentylamino motif, a range of amines were used to open epoxide intermediate 5, providing the amino alcohol derivatives shown after boc-deprotection. No increase in activity was observed from this set, however, in comparison with the original hit compound (Scheme 1B). The contribution of the THIQ mediated cation−π interaction is apparent from this early data set with a number of non-THIQ co...

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confidence: 99%

Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666

Duncan

Rioux

Boriack-Sjodin

et al. 2015

ACS Med. Chem. Lett.

116

108

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“…Through high‐throughput screening of their compound libraries, they have identified a benzodiazepinone having micromolar affinity for the human CGPR receptor exhibiting an antagonist activity in cells. From this compound, several SAR studies were conducted 238–242 and one compound, MK‐0974 (telcagepant, Figure 28A) was chosen to enter a clinical trial 243 . This compound was shown to have good affinity for the CGRP receptor ( K i = 0.77 nM) as well as good oral bioavailability (%F = 45), but a limited CNS exposure.…”

Section: Activity On G Protein‐coupled Receptors (Gpcrs)mentioning

confidence: 99%

1,3‐Diazepine: A privileged scaffold in medicinal chemistry

Malki

Martinez

Masurier

2021

Medicinal Research Reviews

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Privileged structures have been widely used as effective templates for drug discovery. While benzo‐1,4‐diazepine constitutes the first historical example of such a structure, the 1,3 analogue is just as rich in terms of applications in medicinal chemistry. The 1,3‐diazepine moiety is present in numerous biological active compounds including natural products, and is used to design compounds displaying a large range of biological activities. It is present in the clinically used anticancer compound pentostatin, in several recent FDA approved β‐lactamase inhibitors (e.g., avibactam) and also in coformycin, a natural product known as a ring‐expanded purine analogue displaying antiviral and anticancer activities. Several other 1,3‐diazepine containing compounds have entered into clinical trials. This heterocyclic structure has been and is still widely used in medicinal chemistry to design enzyme inhibitors, GPCR ligands, and so forth. This review endeavours to highlight the main use of the 1,3‐diazepine scaffold and its derivatives, and their applications in medicinal chemistry, drug design, and therapy. We will focus more particularly on the development of enzyme inhibitors incorporating this scaffold, with a strong emphasis on the molecular interactions involved in the inhibition mechanism.

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“…Key reactions are the coupling of pyridine derivatives and piperidine compounds. 55,56 On the basis of the stereochemistry of alcohol 51, a double inversion strategy was used to preserve the absolute configuration of 7. After TIPS removal, the alcohol 54 was coupled with 53 to give rimegepant (7).…”

Section: Byfavo™ (Remimazolam)mentioning

confidence: 99%

“…In addition, “right‐hand side” fragment 53 that incorporates key hydrogen‐bonding functionality was obtained via five steps from pyridine derivatives. Key reactions are the coupling of pyridine derivatives and piperidine compounds 55,56 . On the basis of the stereochemistry of alcohol 51 , a double inversion strategy was used to preserve the absolute configuration of 7 .…”

Section: Nurtec Odt™ (Rimegepant)mentioning

confidence: 99%

New pharmaceuticals approved by FDA in 2020: Small‐molecule drugs derived from amino acids and related compounds

et al. 2021

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Calcitonin gene-related peptide (CGRP) receptor antagonists: Pyridine as a replacement for a core amide group

Cited by 20 publications

References 16 publications

Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666

Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666

1,3‐Diazepine: A privileged scaffold in medicinal chemistry

New pharmaceuticals approved by FDA in 2020: Small‐molecule drugs derived from amino acids and related compounds

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