Delving into the Latest Updates on MK-0893 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

GCGR

Mechanism

GCGR antagonists(Glucagon receptor antagonists)

Therapeutic Areas

Endocrinology and Metabolic Disease

Active Indication-

Inactive Indication

Diabetes Mellitus, Type 2

Originator Organization

Merck & Co., Inc.

Active Organization-

Inactive Organization

Merck Sharp & Dohme Corp.

Merck & Co., Inc.Merck GmbH

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC32H27Cl2N3O4

InChIKeyDNTVJEMGHBIUMW-IBGZPJMESA-N

CAS Registry870823-12-4

A novel series of indazole/indole derivatives were discovered as glucagon receptor (GCGR) antagonists through scaffold hopping based on two literature leads: MK-0893 and LY-2409021. Further structure-activity relationship (SAR) exploration and optimization led to the discovery of multiple potent GCGR antagonists with excellent pharmacokinetic properties in mice and rats, including low systemic clearance, long elimination half-life, and good oral bioavailability. These potent GCGR antagonists could be used for potential treatment of type II diabetes.

01 Mar 2019·Journal of Biological ChemistryQ2 · BIOLOGY

Nonconventional glucagon and GLP-1 receptor agonist and antagonist interplay at the GLP-1 receptor revealed in high-throughput FRET assays for cAMP

Q2 · BIOLOGY

Article

Author: Milliken, Brandon T ; Liapakis, George ; Leech, Colin A ; Holz, George G ; Doyle, Robert P ; Chepurny, Oleg G ; Matsoukas, Minos-Timotheos

G protein-coupled receptors (GPCRs) for glucagon (GluR) and glucagon-like peptide-1 (GLP-1R) are normally considered to be highly selective for glucagon and GLP-1, respectively. However, glucagon secreted from pancreatic α-cells may accumulate at high concentrations to exert promiscuous effects at the β-cell GLP-1R, as may occur in the volume-restricted microenvironment of the islets of Langerhans. Furthermore, systemic administration of GluR or GLP-1R agonists and antagonists at high doses may lead to off-target effects at other receptors. Here, we used molecular modeling to evaluate data derived from FRET assays that detect cAMP as a read-out for GluR and GLP-1R activation. This analysis established that glucagon is a nonconventional GLP-1R agonist, an effect inhibited by the GLP-1R orthosteric antagonist exendin(9-39) (Ex(9-39)). The GluR allosteric inhibitors LY2409021 and MK 0893 antagonized glucagon and GLP-1 action at the GLP-1R, whereas des-His¹-[Glu⁹]glucagon antagonized glucagon action at the GluR, while having minimal inhibitory action versus glucagon or GLP-1 at the GLP-1R. When testing Ex(9-39) in combination with des-His¹-[Glu⁹]glucagon in INS-1 832/13 cells, we validated a dual agonist action of glucagon at the GluR and GLP-1R. Hybrid peptide GGP817 containing glucagon fused to a fragment of peptide YY (PYY) acted as a triagonist at the GluR, GLP-1R, and neuropeptide Y2 receptor (NPY2R). Collectively, these findings provide a new triagonist strategy with which to target the GluR, GLP-1R, and NPY2R. They also provide an impetus to reevaluate prior studies in which GluR and GLP-1R agonists and antagonists were assumed not to exert promiscuous actions at other GPCRs.

01 Aug 2017·Genomics, Proteomics & BioinformaticsQ1 · BIOLOGY

Paralog-Divergent Features May Help Reduce Off-Target Effects of Drugs: Hints from Glucagon Subfamily Analysis

Q1 · BIOLOGY

ArticleOA

Author: Yangyun Zou ; Zhixi Su ; Jingqi Zhou ; Xun Gu ; Zhining Sa

AbstractSide effects from targeted drugs remain a serious concern. One reason is the nonselective binding of a drug to unintended proteins such as its paralogs, which are highly homologous in sequences and have similar structures and drug-binding pockets. To identify targetable differences between paralogs, we analyzed two types (type-I and type-II) of functional divergence between two paralogs in the known target protein receptor family G-protein coupled receptors (GPCRs) at the amino acid level. Paralogous protein receptors in glucagon-like subfamily, glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R), exhibit divergence in ligands and are clinically validated drug targets for type 2 diabetes. Our data showed that type-II amino acids were significantly enriched in the binding sites of antagonist MK-0893 to GCGR, which had a radical shift in physicochemical properties between GCGR and GLP-1R. We also examined the role of type-I amino acids between GCGR and GLP-1R. The divergent features between GCGR and GLP-1R paralogs may be helpful in their discrimination, thus enabling the identification of binding sites to reduce undesirable side effects and increase the target specificity of drugs.

100 Deals associated with MK-0893

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12044

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	Phase 2	US	Merck GmbH	-
Diabetes Mellitus, Type 2	Phase 2	US	Merck GmbH	-
Diabetes Mellitus, Type 2	Phase 2	EU	Merck GmbH	-
Diabetes Mellitus, Type 2	Discovery	EU	Merck GmbH	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02004886 (0893-005, CTgov)	Phase 2	Diabetes Mellitus, Type 2	74	Placebo+MK-0893 (MK-0893 (40 mg))	exrwwntngo(syiqnhmjbr) = kyxryajpwr gsfiowcujd (xmkmtksgks, nrsdshrgjx - usvgsqfbgi) View more	-	18 Mar 2014
				Placebo+MK-0893 (MK-0893 (120 mg))	exrwwntngo(syiqnhmjbr) = wrwbmdixtc gsfiowcujd (xmkmtksgks, rkegrryxlq - crlqhxnhxv) View more
NCT00902161 (0893-019, CTgov)	Phase 1	Diabetes Mellitus, Type 2	22	MK0893+Propanolol (MK0893 + Propanolol)	hvlvtewzhe(krevgsokbf) = gpbpnsmcao ppsvrmmmzs (ciavbfsdfm, orjkbymlth - txssldrema) View more	-	08 May 2012
				Placebo+Propanolol (Placebo + Propanolol)	hvlvtewzhe(krevgsokbf) = xxwsmacequ ppsvrmmmzs (ciavbfsdfm, tstmvgessm - sxtxuywmzs) View more
NCT00631488 (0893-015, CTgov)	Phase 2	Diabetes Mellitus, Type 2	146	Placebo for Metformin+Sitagliptin+MK-0893 (MK-0893 + Sitagliptin)	qlzcbeldeb(ltzmzjwaoz) = abymwmwncq fkegybvzzb (rxcrywuuwc, bfdjaugpxd - wemcodhhsn) View more	-	17 Feb 2012
				Placebo for Sitagliptin+MK-0893+Metformin (MK-0893 + Metformin)	qlzcbeldeb(ltzmzjwaoz) = pizunksegg fkegybvzzb (rxcrywuuwc, jvtrtxetnb - wfssvnulzc) View more
NCT00479466 (0893-008, CTgov)	Phase 2	Diabetes Mellitus, Type 2	342	Placebo to MK0893+Placebo to Metformin (Placebo)	(bhhzlnllac) = lckxqyrqew kufnlfhmql (zoaplgqyef, mwwwmvynnz - ojvognqvxm) View more	-	11 Nov 2011
				MK0893+Placebo to Metformin (MK0893 20 mg)	(bhhzlnllac) = aeuicmpbrt kufnlfhmql (zoaplgqyef, vjtnvxdcjc - livuwokbtq) View more