Metabolism-guided drug design

Stepan, Antonia F.; Mascitti, Vincent; Beaumont, Kevin; Kalgutkar, Amit S.

doi:10.1039/c2md20317k

Cited by 97 publications

(92 citation statements)

References 105 publications

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“…[18] A common approach to decrease metabolic instability is the geminal dimethylation of metabolically labile regions. [19] The dimethylated analogue 28 did not show improved metabolic stability but displayed an approximate 20-fold improvement in potency relative to hit compound 1 (Table 3). …”

Section: Resultsmentioning

confidence: 99%

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Substituted Aminoacetamides as Novel Leads for Malaria Treatment

et al. 2019

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Herein we describe the optimization of a phenotypic hit against Plasmodium falciparum based on an aminoacetamide scaffold. This led to N-(3-chloro-4-fluorophenyl)-2-methyl-2-{[4-methyl-3-(morpholinosulfonyl)phenyl]amino}propanamide (compound 28) with low-nanomolar activity against the intraerythrocytic stages of the malaria parasite, and which was found to be inactive in a mammalian cell counter-screen up to 25 μm. Inhibition of gametes in the dual gamete activation assay suggests that this family of compounds may also have transmission blocking capabilities. Whilst we were unable to optimize the aqueous solubility and microsomal stability to a point at which the aminoacetamides would be suitable for in vivo pharmacokinetic and efficacy studies, compound 28 displayed excellent antimalarial potency and selectivity; it could therefore serve as a suitable chemical tool for drug target identification.

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Section: Resultsmentioning

confidence: 99%

“…It should also be noted that compounds with very low log P values are likely to have a large free unbound fraction, which could lead to higher levels of clearance in vivo. [19] …”

Section: Resultsmentioning

confidence: 99%

Substituted Aminoacetamides as Novel Leads for Malaria Treatment

et al. 2019

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“…The organic layers were combined, dried over MgSO 4 , filtered, and concentrated under reduced pressure to afford the corresponding carboxylic acid intermediates 13a, 13b, 13c, and 13d. General Procedure B1 for the Synthesis of Compounds 1,2,15,16,19,20,21,22,23,27, and 50. To a solution of the relevant carboxylic acid (13a, 13b, 13c, or 13d) (1 equiv) in DCM under nitrogen was added DMF (0.01 equiv) then oxalyl chloride (2 equiv).…”

Section: -[2-(35-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carbmentioning

confidence: 99%

Discovery and Optimization of an Azetidine Chemical Series As a Free Fatty Acid Receptor 2 (FFA2) Antagonist: From Hit to Clinic

et al. 2014

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FFA2, also called GPR43, is a G-protein coupled receptor for short chain fatty acids which is involved in the mediation of inflammatory responses. A class of azetidines was developed as potent FFA2 antagonists. Multiparametric optimization of early hits with moderate potency and suboptimal ADME properties led to the identification of several compounds with nanomolar potency on the receptor combined with excellent pharmacokinetic (PK) parameters. The most advanced compound, 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid 99 (GLPG0974), is able to inhibit acetate-induced neutrophil migration strongly in vitro and demonstrated ability to inhibit a neutrophil-based pharmacodynamic (PD) marker, CD11b activation-specific epitope [AE], in a human whole blood assay. All together, these data supported the progression of 99 toward next phases, becoming the first FFA2 antagonist to reach the clinic.

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“…[Fe III Pc] promotes C–H alkylation adjacent to chromene and indole heterocycles ( 20–21 ), and tolerates lactam and thiophene motifs ( 23–24 ). A substrate containing a benzodioxole moiety is readily alkylated ( 22 ), despite the activated methylenedioxy functionality 2a (Fig. 1A).…”

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confidence: 99%

Catalytic C(sp³)–H Alkylation via an Iron Carbene Intermediate

et al. 2017

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The catalytic transformation of a C(sp3)–H bond to a C(sp3)–C bond via an iron carbene intermediate represents a long-standing challenge. Despite the success of enzymatic and small molecule iron catalysts mediating challenging C(sp3)–H oxidations and aminations via high-valent iron oxos and nitrenes, C(sp3)–H alkylations via isoelectronic iron carbene intermediates have thus far been unsuccessful. Iron carbenes have been inert, or shown to favor olefin cyclopropanation and heteroatom-hydrogen insertion. Herein we report an iron phthalocyanine-catalyzed alkylation of allylic and benzylic C(sp3)–H bonds. Mechanistic investigations support that an electrophilic iron carbene mediates homolytic C–H cleavage and rebounds from the resulting organoiron intermediate to form the C–C bond; both steps are tunable via catalyst modifications. These studies suggest that for iron carbenes, distinct from other late metal carbenes, C–H cleavage is partially rate-determining and must be promoted to effect reactivity.

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Metabolism-guided drug design

Cited by 97 publications

References 105 publications

Substituted Aminoacetamides as Novel Leads for Malaria Treatment

Substituted Aminoacetamides as Novel Leads for Malaria Treatment

Discovery and Optimization of an Azetidine Chemical Series As a Free Fatty Acid Receptor 2 (FFA2) Antagonist: From Hit to Clinic

Catalytic C(sp³)–H Alkylation via an Iron Carbene Intermediate

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Metabolism-guided drug design

Cited by 97 publications

References 105 publications

Substituted Aminoacetamides as Novel Leads for Malaria Treatment

Substituted Aminoacetamides as Novel Leads for Malaria Treatment

Discovery and Optimization of an Azetidine Chemical Series As a Free Fatty Acid Receptor 2 (FFA2) Antagonist: From Hit to Clinic

Catalytic C(sp3)–H Alkylation via an Iron Carbene Intermediate

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Catalytic C(sp³)–H Alkylation via an Iron Carbene Intermediate