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Bioorg Med Chem Lett. 2014 Aug 1;24(15):3609-13. doi: 10.1016/j.bmcl.2014.05.024. Epub 2014 May 16.

Discovery of a novel series of potent MK2 non-ATP competitive inhibitors using 1,2-substituted azoles as cis-amide isosteres.

Author information

1
Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: dong.xiao@merck.com.
2
Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
3
In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.

Abstract

A unified strategy was conceived and implemented to deliver conformationally constrained anilides based on their preferred cis-amide conformers. The imidazole/triazole mimicing amide bonds were designed, building upon an earlier discovery of a novel series of tricyclic lactams MK2 kinase inhibitors. This approach enabled rapid, modular synthesis of structurally novel analogs. The efficient SAR development led to the discovery of low molecular weight and potent MK2 non-ATP competitive inhibitors with good ligand efficiency, which led to improved permeability and oral exposure in rats.

KEYWORDS:

Amide bond isostere; Conformational constraint; Ligand efficiency; MK2 inhibitors; cis-Amide bond

PMID:
24913714
DOI:
10.1016/j.bmcl.2014.05.024
[Indexed for MEDLINE]

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