Delving into the Latest Updates on ACHN-975 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

LpxC

Mechanism

LpxC inhibitors(UDP-3-O-acyl-N-acetylglucosamine deacetylase inhibitors)

Therapeutic Areas-

Active Indication-

Inactive Indication-

Originator Organization

Achaogen, Inc.

Active Organization-

Inactive Organization

Achaogen, Inc.

Drug Highest PhaseDiscontinuedPhase 1

First Approval Date-

Regulation-

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Structure

Molecular FormulaC20H23N3O4

InChIKeyGOCUUDXEOKIQRU-IXDOHACOSA-N

CAS Registry1410809-36-7

Author: Boggs, Jen ; Nieto, Vincent ; Joly, Kristin ; Kane, Timothy R. ; Phan, Thu ; Machajewski, Timothy D. ; Seroogy, Julie ; Yang, Wen ; Dozzo, Paola ; Zhu, Hai ; Aggen, James B. ; Shakhmin, Anton ; Moser, Heinz E. ; Wlasichuk, Kenneth ; Linsell, Martin S. ; Holt, Melissa C. ; Cohen, Frederick ; Plato, Craig ; Jubb, Adrian ; Miroshnikova, Olga ; Krause, Kevin M. ; Wang, Zhan ; Konradi, Andrei W. ; Assar, Zahra ; Cirz, Ryan T. ; Zhou, Xiaoming ; Serio, Alisa W. ; Hildebrandt, Darin J. ; Easterday, Ashton N. ; Haglund, Cat M. ; Stein, Adam J. ; Kamal, Zeeshan ; Sun, Alex D. ; Choi, Taylor ; Sviridov, Serguei ; Andrews, Logan D.

AbstractUDP‐3‐O‐(R‐3‐hydroxymyristoyl)‐N‐acetylglucosamine deacetylase (LpxC) is a Zn2+ deacetylase that is essential for the survival of most pathogenic Gram‐negative bacteria. ACHN‐975 (N‐((S)‐3‐amino‐1‐(hydroxyamino)‐3‐methyl‐1‐oxobutan‐2‐yl)‐4‐(((1R,2R)‐2‐(hydroxymethyl)cyclopropyl)buta‐1,3‐diyn‐1‐yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose‐limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN‐975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC‐516, (S)‐N‐(2‐(hydroxyamino)‐1‐(3‐methoxy‐1,1‐dioxidothietan‐3‐yl)‐2‐oxoethyl)‐4‐(6‐hydroxyhexa‐1,3‐diyn‐1‐yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30 mg mL−1 for parenteral administration and conversion into the active drug with a t1/2 of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.

02 Nov 2017·Expert Opinion on Therapeutic PatentsQ2 · MEDICINE

LpxC inhibitors: a patent review (2010-2016)

Q2 · MEDICINE

Review

Author: Kalinin, Dmitrii V. ; Holl, Ralph

INTRODUCTIONThe Zn²⁺-dependent deacetylase LpxC is an essential enzyme of lipid A biosynthesis in Gram-negative bacteria and a promising target for the development of antibiotics selectively combating Gram-negative pathogens. Researchers from industry and academia have synthesized structurally diverse LpxC inhibitors, exhibiting different LpxC inhibitory and antibacterial activities. Areas covered: A brief introduction into the structure and function of LpxC, showing its suitability as antibacterial target, along with the structures of several reported LpxC inhibitors, is given. The article reviews patents (reported between 2010 and 2016) and related research publications on novel small-molecule LpxC inhibitors. Emphasis is placed on structure-activity relationships within the reported series of LpxC inhibitors. Expert opinion: The performed analysis of patents revealed that the current search for novel LpxC inhibitors is focused on small molecules, sharing common structural features like a Zn²⁺-chelating group as well as a highly lipophilic side-chain. However, despite the promising preclinical data of many of the reported compounds, besides the recently withdrawn clinical candidate ACHN-975, no other LpxC inhibitor has entered clinical trials. The lack of clinical candidates might be related with undesired effects caused by the common structural elements of the LpxC inhibitors.

30 Jun 2016·Current Topics in Medicinal ChemistryQ4 · MEDICINE

Insights into the Zinc-Dependent Deacetylase LpxC: Biochemical Properties and Inhibitor Design

Q4 · MEDICINE

Review

Author: Holl, Ralph ; Kalinin, Dmitrii V.

The bacterial enzyme UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC), catalyzing the first committed step of lipid A biosynthesis, represents a promising target in the development of novel antibiotics against Gram-negative bacteria. Structure, catalytic reaction mechanism and regulation of the Zn2+-dependent metalloamidase have been intensively investigated. The enzyme is required for growth and viability of Gram-negative bacteria, displays no sequence homology with any mammalian protein, but is highly conserved in Gram-negative bacteria, thus permitting the development of Gram-negative selective antibacterial agents with limited off-target effects. Several smallmolecule LpxC inhibitors have been developed, like the substrate analog TU-514 (12a), the aryloxazoline L-161,240 (13w), the sulfonamide BB-78485 (23a), the N-aroyl-L-threonine derivative CHIR-090 (24a), the sulfone-containing pyridone LpxC-3 (43e), and the uridine-based inhibitor 1-68A (47a), displaying diverse inhibitory and antibacterial activities. Most of these compounds share a Zn2+-binding hydroxamate moiety attached to a structural element addressing the hydrophobic tunnel or the UDP binding site. The butadiynyl derivative ACHN-975 (28) is the first LpxC inhibitor entering clinical trials.

100 Deals associated with ACHN-975

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