Delving into the Latest Updates on BI-135585 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [1]

Target

11β-HSD

Mechanism

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

Therapeutic Areas

Endocrinology and Metabolic Disease

Active Indication

Diabetes Mellitus, Type 2

Inactive Indication-

Originator Organization

Vitae Pharmaceuticals LLC

Active Organization

Vitae Pharmaceuticals LLCC.H. Boehringer Sohn AG & Co. KG

Inactive Organization

Boehringer Ingelheim GmbH

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

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Structure

Molecular FormulaC28H34N2O5

InChIKeyRYMUARXBHUNLAU-DZGIFAGBSA-N

CAS Registry1374032-89-9

View All Structures (2)

Author: Himmelsbach, Frank ; Leftheris, Katerina ; Meng, Shi ; Xu, Zhenrong ; Kruk, Barbara A ; Zhao, Wei ; Johnson, Judith A ; Lala, Deepak ; Hamilton, Bradford ; Ye, Yuan-Jie ; Zhao, Yi ; Guo, Rong ; Schuler-Metz, Annette ; Singh, Suresh B ; Zhuang, Linghang ; McGeehan, Gerard M ; Claremon, David A ; Schauerte, Heike ; Krosky, Paula M ; Gregg, Richard ; Howard, Lamont ; Cacatian, Salvacion ; McKeever, Brian M ; Lindblom, Peter ; Tice, Colin M ; Bukhtiyarov, Yuri ; Panemangalore, Reshma ; Guo, Joan

A potent, in vivo efficacious 11β hydroxysteroid dehydrogenase type 1 (11β HSD1) inhibitor (11j) has been identified. Compound 11j inhibited 11β HSD1 activity in human adipocytes with an IC₅₀ of 4.3nM and in primary human adipose tissue with an IC₈₀ of 53nM. Oral administration of 11j to cynomolgus monkey inhibited 11β HSD1 activity in adipose tissue. Compound 11j exhibited >1000× selectivity over other hydroxysteroid dehydrogenases, displays desirable pharmacodynamic properties and entered human clinical trials in 2011.

01 May 2016·Diabetes, Obesity and MetabolismQ2 · MEDICINE

Safety, pharmacokinetics and pharmacodynamics of BI 135585, a selective 11β‐hydroxysteroid dehydrogenase‐1 (HSD1) inhibitor in humans: liver and adipose tissue 11β‐HSD1 inhibition after acute and multiple administrations over 2 weeks

Q2 · MEDICINE

Article

Author: Woerle, H.‐J. ; Jungnik, A. ; Freude, S. ; Rauch, T. ; Hamilton, B. ; Schölch, C. ; Huang, F. ; Graefe‐Mody, U. ; Heise, T.

AimsTo assess the safety and pharmacokinetic and pharmacodynamic characteristics of BI 135585, a selective 11β‐hydroxysteroid dehydrogenase‐1 (11β‐HSD1) inhibitor, after single‐ and repeated‐dose administration.MethodsThe single‐dose study included open‐label administration of 200 mg BI 135585 in healthy volunteers, while in the multiple‐dose study, we carried out randomized, double‐blind administration of 5–200 mg BI 135585 or placebo once daily over 14 days in patients with type 2 diabetes (T2DM). Assessments included 11β‐HSD1 inhibition in the liver (urinary tetrahydrocortisol (THF)/tetrahydrocotisone (THE) ratio) and in subcutaneous adipose tissue (AT) ex vivo and determination of hypothalamus‐pituitary‐adrenal (HPA) axis hormone levels.ResultsNo major safety issues occurred with BI 135585 administration. The HPA axis was mildly activated with slightly increased, but still normal adrenocorticotropic hormone levels, increased total urinary corticoid excretion but unchanged plasma cortisol levels. After multiple doses of 5–200 mg BI 135585, exposure (area under the curve) increased dose‐proportionally and half‐life was 55–65 h. The urinary THF/THE ratio decreased, indicating liver 11β‐HSD1 inhibition. Median 11β‐HSD1 enzyme inhibition in the AT reached 90% after a single dose of BI 135585, but was low (31% or lower) after 14 days of continuous treatment.ConclusionsBI 135585 was safe and well tolerated over 14 days and can be dosed once daily. Future studies are required to clarify the therapeutic potential of BI 135585 in view of its effects on 11β‐HSD1 inhibition in AT after single and multiple doses. Enzyme inhibition in the AT was not adequately predicted by the urinary THF/THE ratio.

01 Jan 2015·European Journal of PharmacologyQ3 · MEDICINE

Pharmacological characterization of the selective 11β-hydroxysteroid dehydrogenase 1 inhibitor, BI 135585, a clinical candidate for the treatment of type 2 diabetes

Q3 · MEDICINE

Article

Author: Claremon, David A ; Zhuang, Linghang ; Zhao, Yi ; Lala, Deepak S ; Guo, Joan ; Schuler-Metz, Annette ; Krosky, Paula ; Hamilton, Bradford S ; McGeehan, Gerard M ; Nar, Herbert ; Meng, Shi ; Guo, Rong ; Himmelsbach, Frank

To combat the increased morbidity and mortality associated with the developing diabetes epidemic new therapeutic interventions are desirable. Inhibition of intracellular cortisol generation from cortisone by blocking 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) has been shown to ameliorate the risk factors associated with the metabolic syndrome. A challenge in developing 11β-HSD1 inhibitors has been the species selectivity of small molecules, as many compounds are primate specific. Here we describe our strategy to identify potent selective 11β-HSD1 inhibitors while ensuring target engagement in key metabolic tissues, liver and fat. This strategy enabled the identification of the clinical candidate, BI 135585.

100 Deals associated with BI-135585

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