ChemInform Abstract: Inhibition of γ‐Butyrobetaine Hydroxylase by Cyclopropyl‐Substituted γ‐Butyrobetaines.

Petter, Russell C.; Banerjee, S.; Englard, Sasha

doi:10.1002/chin.199040134

Cited by 3 publications

(4 citation statements)

References 1 publication

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“…Earlier attempts to modify the core of GBB with cyclopropyl groups are consistent with crystallographic evidence of an unexploited “cavity B”. We attempted to exploit cavity B with a number of new compounds.…”

Section: Resultsmentioning

confidence: 53%

Targeting Carnitine Biosynthesis: Discovery of New Inhibitors against γ-Butyrobetaine Hydroxylase

et al. 2014

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γ-Butyrobetaine hydroxylase (BBOX) catalyzes the conversion of gamma butyrobetaine (GBB) to l-carnitine, which is involved in the generation of metabolic energy from long-chain fatty acids. BBOX inhibitor 3-(1,1,1-trimethylhydrazin-1-ium-2-yl)propanoate (mildronate), which is an approved, clinically used cardioprotective drug, is a relatively poor BBOX inhibitor and requires high daily doses. In this paper we describe the design, synthesis, and properties of 51 compounds, which include both GBB and mildronate analogues. We have discovered novel BBOX inhibitors with improved IC50 values; the best examples are in the nanomolar range and about 2 orders of magnitude better when compared to mildronate. For six inhibitors, crystal structures in complex with BBOX have been solved to explain their activities and pave the way for further inhibitor design.

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Section: Resultsmentioning

confidence: 53%

Targeting Carnitine Biosynthesis: Discovery of New Inhibitors against γ-Butyrobetaine Hydroxylase

et al. 2014

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“…The shorter analogue 17 was synthesized by hydrolysis of the fully protected precursor 19. 22 The synthesis of the longer analogue 18 involves 1,4-addition of dimethyl methylphosphonate to 2-substituted acrylate ester 20 23 followed by hydrolysis of all the ester groups.…”

Section: Chemistrymentioning

confidence: 99%

“…A solution of 2-(diethoxyphosphoryl)pentanedioic acid 5-tert-butyl ester 1-ethyl ester 19 22 (0.10 g, 0.28 mmol) in 6 M HCl (20 mL) was refluxed overnight. The solvent was removed under reduced pressure and dried by concentrating from toluene (50 mL × 3).…”

Section: -(3-mercaptopropyl)pentanedioic Acid (4d)mentioning

confidence: 99%

Synthesis and Biological Evaluation of Thiol-Based Inhibitors of Glutamate Carboxypeptidase II: Discovery of an Orally Active GCP II Inhibitor

et al. 2003

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A series of 2-(thioalkyl)pentanedioic acids were synthesized and evaluated as inhibitors of glutamate carboxypeptidase II (GCP II, EC 3.4.17.21). The inhibitory potency of these thiol-based compounds against GCP II was found to be dependent on the number of methylene units between the thiol group and pentanedioic acid. A comparison of the SAR of the thiol-based inhibitors to that of the phosphonate-based inhibitors provides insight into the role of each of the two zinc-binding groups in GCP II inhibition. The most potent thiol-based inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (IC(50) = 90 nM), was found to be orally bioavailable in rats and exhibited efficacy in an animal model of neuropathic pain following oral administration.

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“…25-5.23 (m, 1 H), 5.04-4.99 (m, 1 H), 4.95-4.92 (m, 1 H), 4.23-4.20 (m, 1 H), 3.89-3.79 (m, 2 H), 2.05-2.00 (m, 2 H), 1.38-1.34 (m, 2 H) N-{[(1-But-3-en-1-ylcyclopropyl)methoxy]carbonyl}-3-methyl-L-valine (32c). To a stirred solution of 1 M lithium aluminum hydride (LAH) in ether (65.4 mL, 65.4 mmol), at 0 °C and under nitrogen, was added a solution of ethyl 1-but-3-en-1-ylcyclopropanecarboxylate 36 (5.0 g, 29.7 mmol) in anhydrous ether (25 mL) dropwise over 1 h. The reaction solution was then stirred at RT for 15 h, carefully quenched at 0 °C with water (3 mL), 1 M NaOH (11 mL), and water (9 mL). The resulting mixture was dried over Na 2 SO 4 , filtered, and concentrated to give (1-but-3-en-1-ylcyclopropyl)methanol (3.45 g, 92% yield).…”

Section: T H Imentioning

confidence: 99%

Discovery of Vaniprevir (MK-7009), a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor

McCauley¹,

McIntyre²,

Rudd³

et al. 2010

J. Med. Chem.

175

103

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A new class of HCV NS3/4a protease inhibitors which contain a P2 to P4 macrocyclic constraint was designed using a molecular-modeling derived strategy. Exploration of the P2 heterocyclic region, the P2 to P4 linker, and the P1 side chain of this class of compounds via a modular synthetic strategy allowed for the optimization of enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 35b (vaniprevir, MK-7009), which is active against both the genotype 1 and genotype 2 NS3/4a protease enzymes and has good plasma exposure and excellent liver exposure in multiple species.

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ChemInform Abstract: Inhibition of γ‐Butyrobetaine Hydroxylase by Cyclopropyl‐Substituted γ‐Butyrobetaines.

Abstract: Starting with phosphonates such as (I) or (IX), cyclopropyl‐substituted γ‐butyrobetaines, e.g. (VIII) or (X), are prepared.

Cited by 3 publications

References 1 publication

Targeting Carnitine Biosynthesis: Discovery of New Inhibitors against γ-Butyrobetaine Hydroxylase

Targeting Carnitine Biosynthesis: Discovery of New Inhibitors against γ-Butyrobetaine Hydroxylase

Synthesis and Biological Evaluation of Thiol-Based Inhibitors of Glutamate Carboxypeptidase II: Discovery of an Orally Active GCP II Inhibitor

Discovery of Vaniprevir (MK-7009), a Macrocyclic Hepatitis C Virus NS3/4a Protease Inhibitor

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