Abstract:
:Dipeptidyl peptidase IV (DPP-IV) inhibition has the potential to become a valuable therapy for type 2 diabetes. The synthesis and structure-activity relationship of a new DPP-IV inhibitor class, N-substituted-glycyl-2-cyanopyrrolidines, are described as well as the path that led from clinical development compound 1-[2-[5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine (NVP-DPP728, 8c) to its follow-up, 1-[[(3-hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)-pyrrolidine (NVP-LAF237, 12j). The pharmacological profile of 12j in obese Zucker fa/fa rats along with pharmacokinetic profile comparison of 8c and 12j in normal cynomolgus monkeys is discussed. The results suggest that 12j is a potent, stable, selective DPP-IV inhibitor possessing excellent oral bioavailability and potent antihyperglycemic activity with potential for once-a-day administration.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Villhauer EB,Brinkman JA,Naderi GB,Burkey BF,Dunning BE,Prasad K,Mangold BL,Russell ME,Hughes TEdoi
10.1021/jm030091lkeywords:
subject
Has Abstractpub_date
2003-06-19 00:00:00pages
2774-89issue
13eissn
0022-2623issn
1520-4804journal_volume
46pub_type
杂志文章abstract::Novel N-(4-oxochroman-8-yl)amide derivatives 1 were synthesized and tested for their ability to inhibit rabbit small intestinal ACAT (acyl-CoA:cholesterol acyltransferase) in vitro and to lower serum total cholesterol in cholesterol-fed rats in vivo. Among the synthesized compounds, N-(7-alkoxy-4-oxochroman-8-yl)amide...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00016a021
更新日期:1995-08-04 00:00:00
abstract::The EP(3) receptor on the platelet mediates prostaglandin E(2) potentiation of thrombogenic coagonists including collagen and adenosine diphosphate (ADP). A pharmacophore driven approach led to the identification of diverse peri-substituted heterocycles as potent and selective EP(3) receptor antagonists. A simultaneou...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm9005912
更新日期:2010-01-14 00:00:00
abstract::Doxazosin analogues 1-3 and 1a were synthesized and investigated at alpha1-adrenoceptors and PC-3, DU-145, and LNCaP human prostate cancer cells. Compound 1 (cyclodoxazosin) was a potent alpha(1B)-adrenoceptor antagonist displaying antiproliferative activity higher than that of doxazosin in cancer cells in vitro and i...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm8016046
更新日期:2009-08-13 00:00:00
abstract::2,5-Bis(4-guanylphenyl)-1,3-oxazole, 2,5-bis(4-guanylphenyl)-1,3,4-oxadiazole and -1,3,4-thiadiazole, and 3,6-bis(4-guanylphenyl)pyridazine and several of their "cyclic guanyl" analogues have been synthesized. 2,5-Bis(4-guanylphenyl)-1,3-oxazole and -1,3,4-thiadiazole showed good activity, whithout acute toxicity, aga...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00179a022
更新日期:1980-05-01 00:00:00
abstract::Multidrug resistance-associated protein 1 (MRP1/ABCC1) is a very promiscuous transporter. Herein we used topological polar surface area (TPSA), a descriptor defined as the sum of surfaces of polar atoms in a molecule, to analyze drug transport by MRP1. We suggested that compounds with high TPSA are transported while t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm801389m
更新日期:2009-02-26 00:00:00
abstract::A series of conformationally locked N-glycosides having a cis-1,2-fused pyranose-1,3-oxazoline-2-thione structure and bearing different substituents at the exocyclic sulfur has been prepared. The polyhydroxylated bicyclic system was built in only three steps by treatment of the corresponding readily available 1,2-anhy...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm3006178
更新日期:2012-08-09 00:00:00
abstract::The sea anemone peptide APETx2 is a potent and selective blocker of acid-sensing ion channel 3 (ASIC3). APETx2 is analgesic in a variety of rodent pain models, but the lack of knowledge of its pharmacophore and binding site on ASIC3 has impeded development of improved analogues. Here we present a detailed structure-ac...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm501400p
更新日期:2014-11-13 00:00:00
abstract::The adenosine antagonist 9-chloro-2-(2-furanyl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine (CGS15943) binds to human A3 receptors with high affinity (Ki = 14 nM), while it lacks affinity at rat A3 receptors. Acylated derivatives of the 5-amino group and other modifications were prepared in an effort to provide A3 subtype...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm960482i
更新日期:1996-10-11 00:00:00
abstract::Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin and leptin receptor pathways and thus an attractive therapeutic target for diabetes and obesity. Starting with a high micromolar lead compound, structure-based optimization of novel PTP1B inhibitors by extension of the molecule from the enz...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm0702478
更新日期:2007-09-20 00:00:00
abstract::As part of our studies on the design of agonists of the luteinizing hormone-releasing hormone (LH-RH), we have synthesized the [des-Gly-NH2(10)]-LH-RH N-methylhydrazide (1), the corresponding thiosemicarbazide (2), and the N-formyl- (3) N-acetyl- (4) and N-(trifluoroacetyl)hydrazide (5). Analogue 1 may be regarded as ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00134a021
更新日期:1981-02-01 00:00:00
abstract::Studies of molecular structure-carcinogenicity relations for a set of 157 aromatic amines are reported. A computer-assisted approach using pattern-recognition methods was used to develop a series of discriminants for aromatic amino carcinogenic potential. The 157 compounds were divided into subsets according to tumor ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00135a003
更新日期:1981-03-01 00:00:00
abstract::Protein disulfide isomerase (PDI) is responsible for nascent protein folding in the endoplasmic reticulum (ER) and is critical for glioblastoma survival. To improve the potency of lead PDI inhibitor BAP2 (( E)-3-(3-(4-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzonitrile), we designed and synthesized 67 analogues. We determ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.8b01951
更新日期:2019-04-11 00:00:00
abstract::The directional properties of hydrogen bonds play a major role in determining the specificity of intermolecular interactions. An energy function which takes explicit account of these properties has been developed for use in the determination of energetically favorable ligand binding sites on molecules of known structu...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00053a018
更新日期:1993-01-08 00:00:00
abstract::In the present paper, we described the design, synthesis, SAR, and biological profile of a novel spirocyclic sulfone series of γ-secretase inhibitors (GSIs) related to MRK-560. We utilized an additional spirocyclic ring system to stabilize the active chair conformation of the parent γ-secretase inhibitors. The resulti...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b00774
更新日期:2015-11-25 00:00:00
abstract::Toward developing new potential analgesics, this first structure-activity relationship study of opiorphin (H-Gln-Arg-Phe-Ser-Arg-OH), a human peptide inhibiting enkephalin degradation, was performed. A systematic Ala scanning proved that Phe(3) is a key residue for neprilysin and aminopeptidase N (AP-N) ectoenkephalin...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm2012112
更新日期:2012-02-09 00:00:00
abstract::A series of hexadeoxyribonucleotides (6-mers), d(TGGGAG), substituted with a variety of aromatic groups at the 5'-end were synthesized and tested for anti-human immunodeficiency virus type 1 (HIV-1) activity. While unmodified d(TGGGAG) (31) had no anti-HIV-1 activity, compound 23 with a 3,4-di(benzyloxy)benzyl (DBB) g...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm970658w
更新日期:1998-09-10 00:00:00
abstract::The triphosphates of antiviral 2',3'-dideoxynucleosides (ddNs) are the active chemical species that inhibit viral DNA synthesis. The inhibition involves incorporation of ddNMP into DNA and subsequent chain termination. A conceivable strategy for antiviral drugs is to employ nucleoside 5'-triphosphate mimics that can e...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm040101y
更新日期:2005-04-07 00:00:00
abstract::Models for predicting oral drug absorption kinetics were developed by correlating absorption rate constants in humans (K(a)) with computational molecular descriptors. The K(a) values of a set of 22 passively absorbed drugs were derived from human plasma time-concentration profiles using a deconvolution approach. The K...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm051231p
更新日期:2006-06-15 00:00:00
abstract::Among the nonclassical cannabinoids, CP-55,244 (4), which incorporates an axial 14 beta-hydroxymethyl group, is pharmacologically 30 times more potent than its prototype CP-47,497 (2) and 300 times more potent than delta 9-THC (1). It has a high degree of stereoselectivity (about 120:1) with respect to its diastereois...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm960410r
更新日期:1998-01-15 00:00:00
abstract::Novel classical antifolates (3 and 4) and 17 nonclassical antifolates (11-27) were synthesized as antitumor and/or antiopportunistic infection agents. Intermediates for the synthesis of 3, 4, and 11-27 were 2,4-diamino-5-alkylsubstituted-7H-pyrrolo[2,3-d]pyrimidines, 31 and 38, prepared by a ring transformation/ring a...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm800244v
更新日期:2008-08-14 00:00:00
abstract::A novel method, total pharmacophore diversity (ToPD), based on known pharmacophore features for numerically defining molecular similarity or diversity is described. The method captures the 3D shape and functionality of molecules by the analysis of relevant intramolecular distances to generate a short and descriptive p...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm010036h
更新日期:2001-10-25 00:00:00
abstract::The synthesis of a series of 2-, 3-, and 4-substituted benzylamine derivatives is described. These compounds were studied for their effect on experimental cardiac arrhythmias. Many of the derivatives, but in particular 2-(p-methoxyphenylethynyl)benzylamine (3d), alpha,alpha-dimethyl-4y(phenylethynyl)benzylamine (7a), ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00236a006
更新日期:1975-02-01 00:00:00
abstract::(E)-3-[[[[6-(2-Carboxyethenyl)-5-[[8-(4- methoxyphenyl)octyl]oxy]-2-pyridinyl]methyl]thio]methyl]benzoic acid (11, SB 201993) is a novel, potent LTB4 receptor antagonist. Compound 11 arose from a structure-activity study of a series of trisubstituted pyridines that demonstrated LTB4 receptor antagonist activity. The p...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00046a017
更新日期:1994-09-30 00:00:00
abstract::Several compounds having portions of the camptothecin ring system were prepared. These compounds were screened against L1210 lymphoid leukemia with negative results. Two of the analogs which contained the pyridine and hydroxylactone D and E rings were also screened for inhibition of DNA and RNA syntheses in HeLa cells...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00239a024
更新日期:1975-05-01 00:00:00
abstract::An empirical approach to improve the microsomal stability and CYP inhibition profile of lead compounds 1a and 1b led to the identification of 5 (BMS-341) as a dissociated glucocorticoid receptor modulator. Compound 5 showed significant improvements in pharmacokinetic properties and, unlike compounds 1a-b, displayed a ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.5b00257
更新日期:2015-05-28 00:00:00
abstract::5-Alkoxy-3-(N-substituted carbamoly)-1-phenylpyrazoles were prepared and tested for antiinflammatory and hypnotic activity. Four compounds showed antiinflammatory activity and three possessed hypnotic properties. ...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00211a016
更新日期:1977-01-01 00:00:00
abstract::The regulation of lipid metabolism and it's effect on glucose control and diabetes has received intense interest. Hormone-sensitive lipase (HSL) is a vital enzyme in lipid metabolism. A series of novel pyrrolopyrazinediones has been discovered that demonstrate submicromolar activity both in the enzyme assay and in a (...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm020460y
更新日期:2003-03-27 00:00:00
abstract::Building on insights gained from the discovery of the antimalarial ozonide arterolane (OZ277), we now describe the structure-activity relationship (SAR) of the antimalarial ozonide artefenomel (OZ439). Primary and secondary amino ozonides had higher metabolic stabilities than tertiary amino ozonides, consistent with t...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/acs.jmedchem.6b01586
更新日期:2017-04-13 00:00:00
abstract::A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactiva...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm100957a
更新日期:2010-12-09 00:00:00
abstract::Thrombin, a serine protease, plays a central role in the initiation and propagation of thrombotic events. An extensive search for new thrombin inhibitors was performed, using an unconventional approach. Screening of small basic molecules for binding in the recognition pocket of thrombin led to the discovery of (aminoi...
journal_title:Journal of medicinal chemistry
pub_type: 杂志文章
doi:10.1021/jm00049a008
更新日期:1994-11-11 00:00:00