Delving into the Latest Updates on MK-0916 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms-

Target

11β-HSD

Mechanism

11β-HSD inhibitors(11-beta-hydroxysteroid dehydrogenase inhibitors)

Therapeutic Areas

Cardiovascular DiseasesEndocrinology and Metabolic Disease

Active Indication-

Inactive Indication

Diabetes Mellitus, Type 2HypertensionMetabolic Syndrome

Originator Organization

Merck & Co., Inc.

Active Organization-

Inactive Organization

Merck Sharp & Dohme Corp.Merck Sharp & Dohme LLC

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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The objective of this study is to evaluate the safety and efficacy of two investigational drugs (MK-0736 and MK-0916) in lowering blood pressure and body weight in patients with hypertension (high blood pressure).
This is an early phase trial and some specific protocol information is proprietary and not publicly available at this time. (Full information is available to trial participants).

Start Date01 Nov 2005

Sponsor / Collaborator

Merck Sharp & Dohme LLC

NCT00543595 / CompletedPhase 2

MK0916 in Patients With Type 2 Diabetes and Metabolic Syndrome (0916-005)

This study will test the safety and effectiveness of MK0916 in patients with Type 2 Diabetes Mellitus and Metabolic Syndrome.
This is an early phase trial and some specific protocol information is in progress and not publicly available at this time. (Full information is available to trial participants).

Start Date01 Aug 2004

Sponsor / Collaborator

Merck Sharp & Dohme Corp.

100 Clinical Results associated with MK-0916

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100 Translational Medicine associated with MK-0916

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100 Patents (Medical) associated with MK-0916

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5

Literatures (Medical) associated with MK-0916

01 May 2023·The Journal of Clinical Pharmacology

Importance of Target‐Mediated Drug Disposition (TMDD) of Small‐Molecule Compounds and Its Impact on Drug Development—Example of the Class Effect of HSD‐1 Inhibitors

Review

Author: An, Guohua ; Katz, David A.

AbstractWith more potent drug candidates being developed, the incidence of target‐mediated drug disposition (TMDD) in small‐molecule compounds has significantly increased in the past decade. Moreover, TMDD appears to apply to some small‐molecule compound classes. The main purpose of the current review is to increase the awareness of TMDD in a series of small‐molecule inhibitors of 11β‐hydroxysteroid dehydrogenase type 1 (HSD‐1) using ABT‐384, SPI‐62, MK‐0916, BMS‐823778, and BI‐187004 as case examples. Although developed independently by different pharmaceutical companies, these HSD‐1 inhibitors demonstrated strikingly similar nonlinear pharmacokinetic behaviors when wide dose ranges were evaluated in first‐in‐human (FIH) single ascending dose (SAD) and multiple ascending dose (MAD) studies. Recognizing TMDD in small‐molecule compounds is important, as the information can be leveraged to select the appropriate dose regimen, improve clinical trial design, as well as predict pharmacological target occupancy. In this review, we summarize the general pharmacokinetic features that facilitate the recognition of small‐molecule TMDD, provide case examples of specific HSD‐1 inhibitors, highlight the importance of recognizing TMDD of small‐molecule compounds during clinical development, and comment on the importance of utilizing pharmacometric modeling to facilitate the quantitative understanding of small‐molecule compounds exhibiting TMDD.

01 Dec 2013·British Journal of Clinical PharmacologyQ2 · MEDICINE

Pharmacokinetic–pharmacodynamic studies of the 11β‐hydroxysteroid dehydrogenase type 1 inhibitor MK‐0916 in healthy subjects

Q2 · MEDICINE

Article

Author: Lai, Eseng ; Yan, Kerri ; Crumley, Tami M. ; Ramael, Steven ; Zheng, Wei ; Yang, Amy Yifan ; Stone, Julie A. ; Gottesdiener, Keith M. ; Wright, D. Hamish ; Cilissen, Caroline ; Hermanowski‐Vosatka, Anne ; Sun, Li ; Langdon, Ronald B. ; Wenning, Larissa ; Wagner, John A.

AimsTo characterize pharmacokinetic parameters of MK‐0916 and its safety and tolerability in lean, healthy male subjects following single and multiple oral doses. To assess (by stable‐isotope labelling) the in vivo inhibition of cortisone‐to‐cortisol conversion following oral MK‐0916.MethodsData are presented from two randomized, controlled, double‐blind, rising‐dose phase I studies. In the first study, subjects received single oral doses of 0.4–100 mg MK‐0916 (n = 16). In the second study, subjects received 0.2–225 mg MK‐0916 followed by daily doses of 0.2–100 mg for 13 days beginning on day 2 or day 15 (n = 80). Plasma and urine drug concentrations were measured for pharmacokinetic analysis. For pharmacodynamic analysis, concentrations of plasma [13C4]cortisol were measured by high‐pressure liquid chromatography and tandem mass spectrometry following a single oral dose of 5 mg [13C4]cortisone.ResultsDoses ≥3 mg were rapidly absorbed (time at which maximal concentration was achieved in plasma, 1.1–1.8 h). Exposure (measured as the area under the concentration–time curve from 0 to 168 h) increased approximately in proportion to dose. Values for the maximal plasma concentration and the plasma concentration at 24 h increased in excess of dose proportionality at doses <6 mg and roughly in proportion to dose at doses >6 mg. In subjects dosed with 6 mg MK‐0916 once daily for 14 days, the mean trough plasma concentration was 240 nm and in vivo cortisone‐to‐cortisol conversion was inhibited by 84%. The relationship between plasma MK‐0916 and hepatic 11β‐hydroxysteroid dehydrogenase type 1 inhibition was well represented by a simple Emax model with an IC50 of 70.4 nm. Exposure to MK‐0916 was generally well tolerated.ConclusionsThese findings indicate that 11β‐hydroxysteroid dehydrogenase type 1 is effectively inhibited in human subjects by doses of MK‐0916 that are well tolerated.

01 Jan 2013·MetabolismQ1 · MEDICINE

11beta-Hydroxysteroid dehydrogenase type 1 inhibitors: novel agents for the treatment of metabolic syndrome and obesity-related disorders?

Q1 · MEDICINE

Review

Author: Fotini Adamidou ; Panagiotis Anagnostis ; Marina Kita ; Vasilios G. Athyros ; Dimitri P. Mikhailidis ; Niki Katsiki ; Asterios Karagiannis

OBJECTIVEMetabolic syndrome (MetS) and Cushing's syndrome share common features. It has been proposed that increased glucocorticoid activity at peripheral tissues may play a role in the pathogenesis of MetS and obesity-related disorders. It is well-known that intracellular cortisol concentrations are determined not only by plasma levels but also by the activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which catalyzes the conversion of inactive cortisone to active cortisol, especially in the liver and adipose tissue. Another isoenzyme exists, the 11β-hydroxysteroid dehydrogenase type 2, which acts in the opposite direction inactivating cortisol to cortisone in the kidney. This review considers the significance of the 11β-HSD1 inhibition in the treatment of several features of MetS and provides current data about the development of 11β-HSD1 inhibitors, as new agents for this purpose.MATERIALS/METHODSUsing PubMed, we searched for publications during the last 20years regarding the development of 11β-HSD1 inhibitors.RESULTSEmerging data from animal and human studies indicate an association of 11β-HSD1 over-expression with obesity and disorders in glucose and lipid metabolism. This has led to the hypothesis that selective inhibition of 11β-HSD1 could be used to treat MetS and diabetes. Indeed, natural products and older agents such as thiazolidinediones and fibrates seem to exert an inhibitory effect on 11β-HSD1, ameliorating the cardiometabolic profile. In view of this concept, novel compounds, such as adamantyltriazoles, arylsulfonamidothiazoles, anilinothiazolones, BVT2733, INCB-13739, MK-0916 and MK-0736, are currently under investigation and the preliminary findings from both experimental and human studies show a favourable effect on glucose and lipid metabolism, weight reduction and adipokine levels.CONCLUSIONSMany compounds inhibiting 11β-ΗSD1 are under development and preliminary data about their impact on glucose metabolism and obesity-related disorders are encouraging.

100 Deals associated with MK-0916

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Hypertension	Phase 2	-	Merck Sharp & Dohme LLC	01 Nov 2005
Diabetes Mellitus, Type 2	Phase 2	-	Merck Sharp & Dohme Corp.	01 Aug 2004
Metabolic Syndrome	Phase 2	-	Merck Sharp & Dohme Corp.	01 Aug 2004

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00274716 (0736-003, CTgov)	Phase 2	Hypertension	249	Placebo+MK0736 (High BMI:MK-0736 2mg→Placebo)	wcbvmvgbnv(iomfthyold) = vnvxsqirxj mtxfslchfw (xfuojlohcw, vvtrdffzow - simnhcxdfc) View more	-	14 Feb 2014
				Placebo+MK0736 (High BMI:MK-0736 7mg→Placebo)	wcbvmvgbnv(iomfthyold) = namzooaylk mtxfslchfw (xfuojlohcw, gaihobkzvg - bjiwqaauzj) View more