title: Discovery of a novel series of potent MK2 non-ATP competitive inhibitors using 1,2-substituted azoles as cis-amide isosteres.
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.
authors.affiliation: Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. Electronic address: dong.xiao@merck.com.
authors.forename: Dong
authors.initials: D
authors.lastname: Xiao
authors.affiliation: Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Sofolarides
authors.affiliation: Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Degrado
authors.affiliation: Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Shao
authors.affiliation: Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Ashwin
authors.initials: A
authors.lastname: Rao
authors.affiliation: Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Aslanian
authors.affiliation: In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: James
authors.initials: J
authors.lastname: Fossetta
authors.affiliation: In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Tian
authors.affiliation: In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Prashant
authors.initials: P
authors.lastname: Trivedi
authors.affiliation: In Vitro Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lundell
authors.affiliation: Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors.forename: Anandan
authors.initials: A
authors.lastname: Palani
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D001393:Azoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008968:Molecular Conformation; D010539:Permeability / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000577:Amides; D001393:Azoles; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2
keywords: Amide bond isostere; Conformational constraint; Ligand efficiency; MK2 inhibitors; cis-Amide bond