UDP-3--acyl--acetylglucosamine deacetylase (LpxC) is a zinc metalloenzyme that catalyzes the first committed step in the biosynthesis of Lipid A, an essential component of the cell envelope of Gram-negative bacteria. The most advanced, disclosed LpxC inhibitors showing antibacterial activity coordinate zinc through a hydroxamate moiety with concerns about binding to other metalloenzymes. Here, we describe the discovery, optimization, and efficacy of two series of compounds derived from fragments with differing modes of zinc chelation.
View Article and Find Full Text PDFThe global increase in multidrug-resistant pathogens has caused severe problems in the treatment of infections. To overcome these difficulties, the advent of a new chemical class of antibacterial drug is eagerly desired. We aimed at creating novel antibacterial agents against bacterial type II topoisomerases, which are well-validated targets.
View Article and Find Full Text PDFWe previously reported that MGS0008 is a selective group II metabotropic glutamate receptor (mGlu2/3 receptor) agonist that is effective in animal models of schizophrenia. MGS0008 is a highly hydrophilic glutamate analog and is therefore expected to show low oral bioavailability in humans. To improve the oral bioavailability of MGS0008, ester prodrugs of MGS0008 were synthesized and their usefulness was evaluated.
View Article and Find Full Text PDFDNA gyrase and topoisomerase IV are well-validated pharmacological targets, and quinolone antibacterial drugs are marketed as their representative inhibitors. However, in recent years, resistance to these existing drugs has become a problem, and new chemical classes of antibiotics that can combat resistant strains of bacteria are strongly needed. In this study, we applied our hit-to-lead (H2L) chemistry for the identification of a new chemical class of GyrB/ParE inhibitors by efficient use of thermodynamic parameters.
View Article and Find Full Text PDFThe design and synthesis of a novel class of 7-azaspiro[3.5]nonane GPR119 agonists are described. In this series, optimization of the right piperidine N-capping group (R) and the left aryl group (R) led to the identification of compound 54g as a potent GPR119 agonist.
View Article and Find Full Text PDFThe design, synthesis, and structure activity relationships of the novel class of pyrazolylethylbenzamide orexin receptor 1-selective antagonists are described. Further derivatization of the prototype dual orexin receptor 1/2 antagonist lead (1) by installing a (S)-methyl group into the ethyl linker moiety between the pyrazole ring and benzamide resulted in an increase of the antagonist potency against orexin receptor 1/2 receptors. Optimization of the benzamide and pyrazole parts of compounds 2 and 9b led to the identification of N-ethyl-5-fluoro-N-{(2S)-1-[5-(4-fluorophenyl)-2H-tetrazol-2-yl]propan-2-yl}-2-(pyrimidin-2-yl)benzamide (24), which exhibited excellent antagonistic activity against orexin receptor 1 with an IC of 2.
View Article and Find Full Text PDFWe previously reported a novel series of 1H-pyrazolo[3,4-c]pyridine derivatives and the identification of compound 4b as a highly potent GPR119 agonist. However, the advancement of preclinical evaluations of compound 4b is expected to be difficult because of the compound's significantly poor aqueous solubility (0.71μM at pH6.
View Article and Find Full Text PDFVasopressin 1B receptors (VRs) are abundantly expressed in the pituitary, and in vivo PET of VRs was recently enabled by our development of a specific radioligand, C-TASP0434299, derivatized from pyridopyrimidin-4-one. Here, we identified a novel pyridopyrimidin-4-one analog, --butyl-2-[2-(6-C-methoxypyridine-2-yl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-]pyrimidin-3(4)-yl]acetamide (C-TASP0410699, hereafter referred to as C-TASP699), as a potent VR radioligand producing a higher image contrast for the target than C-TASP0434299. In vitro properties of TASP699 were assessed by assaying its affinity for human VR and its selectivity for off-target molecules.
View Article and Find Full Text PDFDesign and synthesis of a novel class of 1H-pyrazolo[3,4-c]pyridine GPR119 receptor agonists are described. Lead compound 4 was identified through the ligand-based drug design approach. Modification of the left-hand aryl group (R(1)) and right-hand piperidine N-capping group (R(2)) led to the identification of compound 24 as a single-digit nanomolar GPR119 agonist.
View Article and Find Full Text PDFA novel pyridopyrimidin-4-one derivative, N-tert-butyl-2-[2-(3-methoxyphenyl)-6-[3-(morpholin-4-yl)propoxy]-4-oxopyrido[2,3-d]pyrimidin-3(4H)-yl]acetamide (TASP0434299), was characterized as a radioligand candidate for arginine vasopressin 1B (V1B) receptor. TASP0434299 exhibited high binding affinities for human and rat V1B receptors with IC50 values of 0.526 and 0.
View Article and Find Full Text PDFOrexins play an important role in sleep/wake regulation, and orexin receptor antagonists are a focus of novel therapy for the treatment of insomnia. We identified 27e (TASP0428980) as a potent dual orexin receptor antagonist through the systematic modification of our original designed lead A. We demonstrated the potent sleep-promoting effects of 27e at ip dose of 3mg/kg in a rat polysomnogram study.
View Article and Find Full Text PDFThe design, synthesis and structure-activity relationships of a novel class of N-phenylpyridone MCH1R antagonists are described. The core part of the N-phenylpyridone structure was newly designed and the side chain moieties that were attached to the core part were extensively explored. As a result of optimization of the N-phenylpyridone leads, we successfully developed the orally available, and brain-penetrable MCH1R selective antagonist 7c, exhibiting excellent anti-obese effect in diet-induced obese (DIO) mice.
View Article and Find Full Text PDFMelanin-concentrating hormone (MCH), which is a neuropeptide expressed in the hypothalamus of the brain, is involved in regulating feeding behavior and energy homeostasis via the MCH(1) receptor in rodents. It is widely considered that MCH(1) receptor antagonists are worthy of development for medical treatment of obesity. Here we report on the development of an ex vivo receptor occupancy assay using a new radiolabeled MCH(1) receptor antagonist, [(35)S]-compound D.
View Article and Find Full Text PDFWe describe design, syntheses and structure-activity relationships of a novel class of 4,6-disubstituted quinazoline glucokinase activators. Prototype quinazoline leads (4 and 5) were designed based on the X-ray analyses of the previous 2-aminobenzamide lead classes. Modifications of the quinazoline leads led to the identification of a potent GK activator (21d).
View Article and Find Full Text PDFNovel phenethylpyridone derivatives were identified as potent human melanin-concentrating hormone 1 receptor (MCH-1R) antagonists. A search for surrogates for the 4-(2-aminoethoxy)phenyl moiety of 1 resulted in discovery of 2-[4-(aminomethyl)phenyl]ethyl substructure as in 6a. Successive optimization of the right-hand moiety led to the identification of a number of potent derivatives.
View Article and Find Full Text PDFA series of 2-pyridone-containing imidazoline derivatives was synthesized and evaluated as neuropeptide Y Y5 receptor antagonists. Optimization of the 2-pyridone structure on the 2-position of the imidazoline ring led to identification of 1-(difluoromethyl)-5-[(4S,5S)-4-(4-fluorophenyl)-4-(6-fluoropyridin-3-yl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl]pyridin-2(1H)-one (7m). Compound 7m displayed statistically significant inhibition of food intake in an agonist-induced food intake model in SD rats and no adverse cardiovascular effects in anesthetized dogs.
View Article and Find Full Text PDFSyntheses and structure-activity relationships of a novel class of 2-[3-oxospiro[isobenzofuran-1(3H),1'-cyclohexan]-4'-yl]benzimidazole NPY Y5 receptor antagonists are described. Optimization of the lead compound 2a by incorporating substituents into the 5-position or into both the 5- and 6-positions of the benzimidazole core part led to the identification of 5-(5-methyl-1,2,4-oxadiazol-2-yl)benzimidazole (2r: IC(50)=3.3 nM) and 5-(2-methyltetrazol-5-yl)benzimidazole (2u: IC(50)=5.
View Article and Find Full Text PDFDesign, syntheses, and structure-activity relationships of a novel class of 2-{3-oxospiro[isobenzofuran-1(3H),4'-piperidin]-1'-yl}benzimidazole NPY Y5 receptor antagonists are described. The benzimidazole structures were newly designed based on the urea linkage of our prototype Y5 receptor antagonists (2 and 3). By optimizing substituents on the benzimidazole core part of the lead compound 5a, we were able to develop a potent, orally available, and brain-penetrable Y5 selective antagonist (5k).
View Article and Find Full Text PDFIdentification of a novel class of potent and highly selective M(3) muscarinic antagonists is described. First, the structure-activity relationship in the cationic amine core of our previously reported triphenylpropionamide class of M(3) selective antagonists was explored by a small diamine library constructed in solid phase. This led to the identification of M(3) antagonists with a novel piperidine pharmacophore and significantly improved subtype selectivity from a previously reported class.
View Article and Find Full Text PDFSynthesis and structure-activity relationship of a new class of muscarinic M(3) selective antagonists were described. In the course of searching for a muscarinic M(3) antagonist with a structure distinct from those of the 2-(4,4-difluorocyclopentyl)-2-phenylacetamide derivatives, we identified a thiazole-4-carboxamide derivative (1) as a lead compound in our in-house chemical collection. Since this compound (1) showed relatively low binding affinity (K(i)=140 nM) for M(3) receptors in the human binding assays, we tried to improve its potency and selectivity for M(3) over M(1) and M(2) receptors by derivatization of 1 through a combinatorial approach.
View Article and Find Full Text PDFThe synthesis and structure-activity relationships of a series of 5,7-diarylcyclopenteno[1,2-b]pyridine-6-carboxylic acids are described. Our efforts have been focused on modification of the aryl ring at the 5-position and the alkyl substituent at the 2-position of the bottom 4-methoxyphenyl ring in an effort to develop orally available ET(A) selective antagonists with safer profiles in terms of the P-450 enzyme inhibitory activity. Incorporation of a hydroxymethyl group as an alkyl substituent in methylenedioxyphenyl and 6-dihydrobenzofuran derivatives led to the identification of orally bioavailable ET(A) selective antagonists 1f and 7f.
View Article and Find Full Text PDFThe synthesis and structure-activity relationships of 6-carboxy-2-isopropylamino-5,7-diarylcyclopenteno[1,2-b]pyridine class of ET(A) receptor selective antagonists were described. These derivatives were prepared from the optically active key intermediates (3, 4, 10, and 13). Optimization of the substituent at the 2-position of the bottom 4-methoxyphenyl ring of the lead compound 1 led to identification of 2-hydroxy-1-methylethoxy (2g and h), hydroxyalkyl (2i, m, and p), 3-methoxy-2-methylpropyl (2t and u), N-acetyl-N-methylaminomethyl (2v), and 2-(dimethylcarbamoyl)propyl (2w) derivatives that showed greater than 1000-fold selectivity for the ET(A) receptor over the ET(B) receptor with excellent binding affinity (IC(50)<0.
View Article and Find Full Text PDFThe identification of potent and selective orexin-2 receptor (OX(2)R) antagonists is described based on the modification of N-acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline analogue 1, recently discovered during high throughput screening (HTS). Substitution of an acyl group in 1 with tert-Leucine (tert-Leu), and introduction of a 4-pyridylmethyl substituent onto the amino function of tert-Leu improved compound potency, selectivity, and water solubility. Thus, compound 29 is a promising tool to investigate the role of orexin-2 receptors.
View Article and Find Full Text PDFThe structure activity relationships of novel selective CCR3 receptor antagonists, 2-(benzothiazolylthio)acetamimde derivatives were described. A lead structure (1a) was discovered from the screening of the focused library that was based on the structure of our dual antagonists for the human CCR1 and CCR3 receptors. Derivatization of 1a including incorporation of substituent(s) into each benzene ring of the benzothiazole and piperidine side chain resulted in the identification of potent and selective compounds (1b, r, s) exhibiting nano-molar binding affinity (IC(50)s: 1.
View Article and Find Full Text PDF