1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(<i>S</i>)-pyrrolidine:  A Potent, Selective, and Orally Bioavailable Dipeptidyl Peptidase IV Inhibitor with Antihyperglycemic Properties

Villhauer, Edwin B.; Brinkman, J. A.; Naderi, Goli B; Burkey, Bryan F.; Dunning, Beth E.; Prasad, Kapa; Mangold, B. L. K.; Russell, Mary E.; Hughes, Thomas E.

doi:10.1021/jm030091l

Cited by 595 publications

(409 citation statements)

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“…Previously we have shown that vildagliptin (also called LAF-237) improves glucose tolerance in high-fat fed glucose intolerant mice (25). Vildagliptin also has been shown to augment the insulin response to oral glucose and glucose tolerance in obese Zucker rats (20) and to improve glucose tolerance in ob/ob mice (26) and Zucker diabetic fatty rats (27). The antidiabetic action of vildagliptin relies on increased concentrations of active (intact) GLP-1, since DPP-4 inhibition prevents the inactivation of the incretin hormone (1-3).…”

Section: Discussionmentioning

confidence: 99%

DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with β-cell-specific overexpression of human islet amyloid polypeptide

Åhrén

Winzell

Wierup

et al. 2007

Regulatory Peptides

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Inhibition of dipeptidyl peptidase-4 (DPP-4) is currently explored as a novel therapy of type 2 diabetes. The strategy has been shown to improve glycemia in most, but not all, rodent forms of glucose intolerance. In this study, we explored the effects of DPP-4 inhibition in mice with β-cell overexpression of human islet amyloid polypeptide (IAPP). We therefore administered the orally active and highly selective DPP-4 inhibitor, vildagliptin (3µmol/mouse daily) to female mice with β-cell overexpression of human IAPP. Controls were given plain water, and a series of untreated wildtype mice was also included. After five weeks, an intravenous glucose tolerance test showed improved glucose disposal and a markedly enhanced insulin response in mice treated with vildagliptin. After eight weeks, a gastric tolerance test showed that vildagliptin improved glucose tolerance and markedly (approximately ten-fold) augmented the insulin response in association with augmented (approximately five-fold) levels of intact glucagon-like peptide-1 (GLP-1). Furthermore, after nine weeks, islets were isolated.Islets from vildagliptin-treated mice showed augmented glucose-stimulated insulin response and a normalization of the islet insulin content, which was reduced by approximately 50% in transgenic controls versus wildtype animals. Double immunostaining of pancreatic islets for insulin and glucagon revealed that transgenic islets displayed severely disturbed intra-islet topography with frequently observed centrally located α-cells. Treatment with vildagliptin restored the islet topography. We therefore conclude that DPP-4 inhibition improves islet function and islet topography in mice with specific ß cell transgenic overexpression of human IAPP.

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Section: Discussionmentioning

confidence: 99%

DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with β-cell-specific overexpression of human islet amyloid polypeptide

Åhrén

Winzell

Wierup

et al. 2007

Regulatory Peptides

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“…Overall, none of the evaluated substituents was able to improve FAP potency significantly, with substituents in the 2-and 3-position of the quinoline ring as in compounds 19−24, having a clearly negative effect on this parameter. Identifying the factors that cause this effect is not evident from these six analogues, but both steric (19,22, and 23) and electronic (20,21, and 24, with an increased electron density in the pyridine ring compared to 7) factors seem to be contributive. Remarkably, PREP-affinity is affected in a more intricate manner by these substitution types: the negative effect of 3-hydroxylation in 20 and 24 significantly contrasts with the influence of a 2-hydroxyl functionality in 21.…”

Section: * S Supporting Informationmentioning

confidence: 92%

Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold

Jansen

Heirbaut

Cheng

et al. 2013

ACS Med. Chem. Lett.

184

147

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Fibroblast activation protein (FAP) is a serine protease that is generally accepted to play an important role in tumor growth and other diseases involving tissue remodeling. Currently there are no FAP inhibitors with reported selectivity toward both the closely related dipeptidyl peptidases (DPPs) and prolyl oligopeptidase (PREP). We present the discovery of a new class of FAP inhibitors with a N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) scaffold. We have explored the effects of substituting the quinoline ring and varying the position of its sp 2 hybridized nitrogen atom. The most promising inhibitors combined low nanomolar FAP inhibition and high selectivity indices (>10 3 ) with respect to both the DPPs and PREP. Preliminary experiments on a representative inhibitor demonstrate that plasma stability, kinetic solubility, and log D of this class of compounds can be expected to be satisfactory.

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“…Moreover, several adamantanebased drugs are currently employed as important medications against malaria infections [7], central nervous disorders [8][9][10], hyperglycaemia [11] and drug-resistant TB strain infections [12]. In addition, thiourea derivatives were reported to display marked antitumor [13], anti-HIV [14], antimalarial [15] and antimicrobial [16] activities.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of 1-(adamantan-1-yl)-3-(4-bromophenyl)thiourea, C₁₇H₂₁BrN₂S

et al. 2016

Zeitschrift Für Kristallographie - New Crystal Structures

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C17H 21 BrN 2 S, orthorhombic, Pbca (No. 61), a = 17.0675(7) Å, CCDC no.: 1449483The asymmetric unit of the crystal structure is shown in the gure. Tables 1 and 2 contain details of the measurement method and a list of the atoms including atomic coordinates and displacement parameters. Source of materialTo a solution of 1-adamantylamine (1.51 g, 0.01 mol) in ethanol (15 mL), 4-bromophenyl isothiocyanate (2.14 g, 0.01 mol) was added and the mixture was heated under re ux for three hours. On cooling, the precipitated crude product was ltered, dried and crystallized from ethanol to yield 3.36 g (92%) of the title compound (C17H 21 BrN 2 S) as transparent block crystals. M.P.:

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1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: A Potent, Selective, and Orally Bioavailable Dipeptidyl Peptidase IV Inhibitor with Antihyperglycemic Properties

Cited by 595 publications

References 63 publications

DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with β-cell-specific overexpression of human islet amyloid polypeptide

DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with β-cell-specific overexpression of human islet amyloid polypeptide

Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold

Crystal structure of 1-(adamantan-1-yl)-3-(4-bromophenyl)thiourea, C₁₇H₂₁BrN₂S

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1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: A Potent, Selective, and Orally Bioavailable Dipeptidyl Peptidase IV Inhibitor with Antihyperglycemic Properties

Cited by 595 publications

References 63 publications

DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with β-cell-specific overexpression of human islet amyloid polypeptide

DPP-4 inhibition improves glucose tolerance and increases insulin and GLP-1 responses to gastric glucose in association with normalized islet topography in mice with β-cell-specific overexpression of human islet amyloid polypeptide

Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold

Crystal structure of 1-(adamantan-1-yl)-3-(4-bromophenyl)thiourea, C17H21BrN2S

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Crystal structure of 1-(adamantan-1-yl)-3-(4-bromophenyl)thiourea, C₁₇H₂₁BrN₂S