Search

A series of IDO1 inhibitors containing a decahydroquinoline, decahydro-1,6-naphthyridine, or octahydro-1H-pyrrolo[3,2-c]pyridine scaffold were identified with good cellular and human whole blood activity against IDO1. These inhibitors contain multiple chiral centers and all diastereomers were separated. The absolute stereochemistry of each isomers were not determined. Compounds 15 and 27 stood out as leads due to their good cellular as well as human whole blood IDO1 inhibition activity, low unbound clearance, and reasonable mean residence time in rat cassette PK studies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The activin-like kinases are a family of kinases that play important roles in a variety of disease states. Of this class of kinases, ALK2, has been shown by a gain-of-function to be the primary driver of the childhood skeletal disease fibrodysplasia ossificans progressiva (FOP) and more recently the pediatric cancer diffuse intrinsic pontine glioma (DIPG). Herein, we report our efforts to identify a novel imidazo[1,2-a]pyridine scaffold as potent inhibitors of ALK2 with good in vivo pharmacokinetic properties suitable for future animal studies., Competing Interests: Declaration of Competing Interest The authors: D.W.E., C.W.L., C.C.H., and C.R.H. have received funding and royalties from La Jolla Pharmaceuticals., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A series of potent, selective and long-acting quinoline-based sulfonamide human H 1 histamine receptor antagonists, designed for once-daily intranasal administration for the treatment of rhinitis were developed. Sulfonamide 33b had a slightly lower affinity for the H 1 receptor than azelastine, had low oral bioavailability in the rat and dog, and was turned over to five major metabolites. Furthermore, 33b had longer duration of action than azelastine in guinea pigs, lower rat brain-penetration, and did not cause time dependent inhibition of CYP2D6 or CYP3A4. The clinical dose in humans is expected to be low (approximately 0.5mg per day) based on the clinical dose used for azelastine and a comparison of efficacy data from animal models for 33b and azelastine., (Copyright © 2017. Published by Elsevier Ltd.)

Background: The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signalling axis and androgen receptor (AR) pathways exhibit reciprocal feedback regulation in phosphatase and tensin homologue (PTEN)-deficient metastatic castration-resistant prostate cancer (CRPC) in preclinical models. This phase Ib study evaluated the pan-PI3K inhibitor buparlisib (BKM120) and the dual pan-PI3K/ mammalian target of rapamycin (mTOR) inhibitor dactolisib (BEZ235) in combination with abiraterone acetate (AA) in patients with CRPC., Materials and Methods: Patients with CRPC who had progressed on AA therapy received escalating doses of either buparlisib or dactolisib, along with fixed doses of AA (1000 mg once daily (qd)) and prednisone (5 mg twice daily (bid)). The primary objective was to define the maximum tolerated dose (MTD) and/or the recommended dose for expansion (RDE) of either buparlisib or dactolisib in combination with AA. Secondary objectives included safety, antitumour activity (Prostate Cancer Working Group 2 (PCWG2) criteria; 30% of prostate-specific antigen (PSA) decline at ≥week 12) and pharmacokinetic (PK) profile., Results: In buparlisib + AA arm, 25 patients received buparlisib + AA (median age, 67 years; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1/2 for 7/17/1 patients, respectively). At 100 mg qd; two patients experienced dose-limiting toxicities (DLTs) (grade 3 hyperglycaemia; grade 2 asthenia), and this was the maximum buparlisib dose explored. Buparlisib + AA showed a 26% lower median area under the curve from time zero to 24°h (AUC 0-24 ) and 48% lower median maximum serum concentration (Cmax) versus the single-agent buparlisib assessed in first-in-human study. No objective response and few PSA decreases were reported. In dactolisib + AA arm, 18 patients (median age, 71 years; ECOG PS of 0/1 for 6/12 patients, respectively) received dactolisib + AA at the first dose level (200 mg bid). Five patients had 9 DLTs (grades 2&3 stomatitis; grade 3 hyperglycaemia; grades 2& 3 diarrhoea; grades 1& 2 pyrexia, grade 2 vomiting, and grade 2 chills)., Conclusions: Based on the assessment of available pharmacokinetics, safety, and efficacy data, no further study is planned for either buparlisib or dactolisib in combination with AA in CRPC., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

This Letter describes the discovery of a series of potent inhibitors of Human Uric Acid Transporter 1 (hURAT1). Lead generation and optimization via 3D pharmacophore analysis resulted in compound 41. With an IC50 of 33.7nM, 41 also demonstrated good oral bioavailability in rat (74.8%) and displayed a consistent PK profile across all species tested (rat, dog and monkey)., (Copyright © 2015. Published by Elsevier Ltd.)

Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-1(VEGFR1), -2(VEGFR2), and -3(VEGFR3). Analog of Tivozanib with deuterium-for-hydrogen replacement in metabolically active site was prepared and evaluated in vitro. Compared to its prototype, deuterated Tivozanib compound HC-1144 retained in vitro activity against VEGFR tyrosine kinases. In vivo pharmacokinetic studies indicated HC-1144 clearly altered the blood circulation behavior, which was proved by significantly prolonged blood circulation half life time (t1/2) and increased AUC0-∞. Therefore, HC-1144 has the potential to be a novel inhibitor against VEGFR tyrosine kinases with long-acting plasma exposure., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

2,3,4-Substituted quinolines such as (10a) were found to be potent inhibitors of PI3Kδ in both biochemical and cellular assays with good selectivity over three other class I PI3K isoforms. Some of those analogs showed favorable pharmacokinetic properties., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In vitro ADME characterization of the lead compound 1 identified for visceral leishmaniasis was undertaken and further structural analogs were synthesized for antileishmanial screening. Compound 1 was highly permeable in intestinal PAMPA model (31 × 10(-6)cm/s) and was moderately bound to mouse and human plasma proteins (% bound 85-95%), its blood to plasma concentration ratio was less than 1, but the compound was unstable in blood. Compound 1 was found to have no CYP450 liability with CYP2C9, 2C19, 2D6 and 3A4. It showed inhibition with CYP1A2 with an IC50 value of 0.50 μM. Analogs of 1 were synthesized and subsequently characterized for in vitro activity against the intracellular form of Leishmania donovani. Resulting quinolines were found to have similar efficacy as 1 against the parasite. Compounds 8b and 8f were found to be the most active with IC50 values of 0.84 μM and 0.17 μM, respectively compared to 0.22 μM for compound 1. Of all the analogs tested, 8d was stable in hamster, mouse and human liver microsomes but lost the efficacy with an IC50 of 6.42 μM. Based on the in vitro efficacy and DMPK profile, compounds 8b and 8f seem the best candidates to be screened in further assays., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

IRAK4 is responsible for initiating signaling from Toll-like receptors (TLRs) and members of the IL-1/18 receptor family. Kinase-inactive knock-ins and targeted deletions of IRAK4 in mice cause reductions in TLR induced pro-inflammatory cytokines and these mice are resistant to various models of arthritis. Herein we report the identification and optimization of a series of potent IRAK4 inhibitors. Representative examples from this series showed excellent selectivity over a panel of kinases, including the kinases known to play a role in TLR-mediated signaling. The compounds exhibited low nM potency in LPS- and R848-induced cytokine assays indicating that they are blocking the TLR signaling pathway. A key compound (26) from this series was profiled in more detail and found to have an excellent pharmaceutical profile as measured by predictive assays such as microsomal stability, TPSA, solubility, and clogP. However, this compound was found to afford poor exposure in mouse upon IP or IV administration. We found that removal of the ionizable solubilizing group (32) led to increased exposure, presumably due to increased permeability. Compounds 26 and 32, when dosed to plasma levels corresponding to ex vivo whole blood potency, were shown to inhibit LPS-induced TNFα in an in vivo murine model. To our knowledge, this is the first published in vivo demonstration that inhibition of the IRAK4 pathway by a small molecule can recapitulate the phenotype of IRAK4 knockout mice., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The discovery of lead compound 2e was described. Its covalent binding to HCV NS5B polymerase enzyme was investigated by X-ray analysis. The results of distribution, metabolism and pharmacokinetics were reported. Compound 2e was demonstrated to be potent (replicon GT-1b EC50 = 0.003 μM), highly selective, and safe in in vitro and in vivo assays., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The optimization of oxazole-based PDE4 inhibitor 1 has led to the identification of both oral (compound 16) and inhaled (compound 34) PDE4 inhibitors. Selectivity against PDE10/PDE11, off target screening, and in vivo activity in the rat are discussed., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A structure-activity relationship of the 3- and 6-positions of the pyrazolo[1,5-a]pyrimidine scaffold of the known BMP inhibitors dorsomorphin, 1, LDN-193189, 2, and DMH1, 3, led to the identification of a potent and selective compound for ALK2 versus ALK3. The potency contributions of several 3-position substituents were evaluated with subtle structural changes leading to significant changes in potency. From these studies, a novel 5-quinoline molecule was identified and designated an MLPCN probe molecule, ML347, which shows >300-fold selectivity for ALK2 and presents the community with a selective molecular probe for further biological evaluation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Aim: To determine the maximum tolerated dose (MTD) of OSI-930 that can be combined with erlotinib, and establish recommended phase 2 doses when both agents are administered daily in patients with advanced solid tumours., Patients and Methods: Eligible patients with advanced solid tumours were enrolled into this standard "three+three" dose escalation study. Study treatment commenced on day 1 with OSI-930, and erlotinib was introduced on day 8. PK profiles of OSI-930, erlotinib and its active metabolite, OSI-420, were determined. Changes in sVEGFR2 as a pharmacodynamic biomarker of OSI-930 activity were assessed., Results: Twenty one patients were enrolled to 1 of 3 cohorts: 200 mg OSI-930 BID+100 mg erlotinib QD; 200 mg OSI-930 BID+150 mg erlotinib QD; 300 mg OSI-930 BID+150 mg erlotinib QD. The most common adverse events were anorexia (85%), diarrhoea (75%), rash (70%) and lethargy (65%). The MTD was not reached but the onset of cumulative toxicity necessitating dose modification after the 28-d DLT assessment period was common at the highest dose level. A PK interaction was identified with co-administration of both agents resulting in a two-fold increase in OSI-930 exposure. Pharmacodynamic activity was observed with a decline in sVEGFR levels detected in all patients. Ten patients had disease stabilization (median duration 119 d)., Conclusions: 200 mg OSI-930 BID+150 mg erlotinib QD were the recommended doses for further evaluation of this combination., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

This letter describes the discovery and SAR optimization of tetrazoyl tetrahydroquinoline derivatives as potent CETP inhibitors. Compound 6m exhibited robust HDL-c increase in hCETP/hApoA1 double transgenic model and favorable pharmacokinetic properties., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The discovery of GS-9451 is reported. Modification of the P3 cap and P2 quinoline with a series of solubilizing groups led to the identification of potent HCV NS3 protease inhibitors with greatly improved pharmacokinetic properties in rats, dogs and monkeys., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

A series of pyrazoloquinolines, possessing (hetero)arylhydroxymethyl substituents at the quinoline C-4 position were evaluated as PDE10A inhibitors. Among these, methylpyrimidyl analogue 15 was identified as having good rodent and monkey exposure, and a MED of 10 mg/kg in an in vivo model., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Cyclic nucleotide phosphodiesterases (PDEs) are represented by a large superfamily of enzymes. A series of hydrazone-based inhibitors was synthesized and shown to be novel, potent, and selective against PDE10A. Optimized compounds of this class were efficacious in animal models of schizophrenia and may be useful for the treatment of this disease., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The insulin-like growth factor-1 receptor (IGF-1R) plays an important role in the regulation of cell growth and differentiation, and in protection from apoptosis. IGF-1R has been shown to be an appealing target for the treatment of human cancer. Herein, we report the synthesis, structure-activity relationships (SAR), X-ray cocrystal structure and in vivo tumor study results for a series of 2,4-bis-arylamino-1,3-pyrimidines., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

SAR studies on the quinolone carboxylic acid class of HIV-1 integrase inhibitors focused on improving the metabolic stability and led to the discovery of 27 and 38., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Opioid receptors play an important role in both behavioral and homeostatic functions. We herein report tetrahydroquinoline derivatives as opioid receptor antagonists. SAR studies led to the identification of the potent antagonist 2v, endowed with 1.58nM (K(i)) functional activity against the μ opioid receptor. DMPK data suggest that novel tetrahydroquinoline analogs may be advantageous in peripheral applications., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKβ. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The present work describes a series of novel tetrahydroquinoline amines that potently inhibit the in vitro reuptake of serotonin and dopamine (dual reuptake inhibitors). The compounds are structurally related to a series we disclosed previously, but are improved with respect to cytochrome P-450 enzyme (CYP) and potassium ion channel Kv11.1 (hERG) inhibition and synthetic accessibility. The detailed synthesis and in vitro activity and ADME profile of the compounds is described, which represent a previously undisclosed dual reuptake inhibitor chemotype., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Despite emergence of resistance to CQ and other 4-aminoquinoline drugs in most of the endemic regions, research findings provide considerable support that there is still significant potential to discover new affordable, safe, and efficacious 4-aminoquinoline antimalarials. In present study, new side chain modified 4-aminoquinoline derivatives and quinoline-acridine hybrids were synthesized and evaluated in vitro against NF 54 strain of Plasmodium falciparum. Among the evaluated compounds, compound 17 (MIC=0.125 μg/mL) was equipotent to standard drug CQ (MIC=0.125 μg/mL) and compound 21 (MIC=0.031 μg/mL) was four times more potent than CQ. Compound 17 showed the curative response to all the treated swiss mice infected with CQ-resistant N-67 strain of Plasmodium yoelii at the doses 50 mg/kg and 25 mg/kg for four days by intraperitoneal route and was found to be orally active at the dose of 100 mg/kg for four days. The promising antimalarial potency of compound 17 highlights the significance of exploring the privileged 4-aminoquinoline class for new antimalarials., (Copyright © 2010. Published by Elsevier Ltd.)

The SAR study of a series of 6-aryloxymethyl-8-aryl substituted quinolines is described. Optimization of the series led to the discovery of compound 26b, a highly potent (IC50=0.6 nM) and selective PDE4D inhibitor with a 75-fold selectivity over the A, B, and C subtypes and over 18,000-fold selectivity against other PDE family members. Rat pharmacokinetics and tissue distribution are also summarized., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Radiosynthesis and in vivo evaluation of [N-methyl-(11)C] 5-methyl-3-[4-(3-phenylallyl)-piperazin-1-ylmethyl]-3,3a,4,5-tetrahydroisoxazolo[4,3-c]quinoline (1), a potential PET tracer for alpha2-adrenergic receptors is described. Syntheses of nonradioactive standard 1 and corresponding desmethyl precursor 2 were achieved from 2-aminobenzaldehyde in 40% and 65% yields, respectively. Methylation using [(11)C]CH(3)I in presence of aqueous potassium hydroxide in DMSO afforded [(11)C]1 in 25% yield (EOS) with >99% chemical and radiochemical purities with a specific activity ranged from 3-4 Ci/micromol (n=6). The total synthesis time was 30 min from EOB. PET studies in anesthetized baboon show that [(11)C]1 penetrates BBB and accumulates in alpha2A-AR enriched brain areas., (Copyright 2010 Elsevier Ltd. All rights reserved.)

A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint was identified. The combination of the quinoline constraint with a tricyclic benzimidazolinone left hand fragment produced an analog with picomolar potency (14, CGRP K(i)=23 pM). Further optimization of the tricycle produced a CGRP receptor antagonist that exhibited subnanomolar potency (19, CGRP K(i)=0.52 nM) and displayed a good pharmacokinetic profile in three preclinical species., (Copyright 2010 Elsevier Ltd. All rights reserved.)

In the course of our efforts to identify orally active cholesteryl ester transfer protein (CETP) inhibitors, we have continued to explore tetrahydrochinoline derivatives. Based on BAY 19-4789 structural modifications led to the discovery of novel cycloalkyl substituted compounds. Thus, example 11b is a highly potent CETP inhibitor both in vitro and in vivo in transgenic mice with favourable pharmacokinetic properties for clinical development., (Copyright 2010 Elsevier Ltd. All rights reserved.)

A series of quinoline-3-carboxamide containing sulfones was prepared and found to have good binding affinity for LXRbeta and moderate binding selectivity over LXRalpha. The 8-Cl quinoline analog 33 with a high TPSA score, displayed 34-fold binding selectivity for LXRbeta over LXRalpha (LXRbeta IC(50)=16nM), good activity for inducing ABCA1 gene expression in a THP macrophage cell line, desired weak potency in the LXRalpha Gal4 functional assay, and low blood-brain barrier penetration in rat., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Species specific conversion of the lead PDE4 inhibitor 1 to the quinolone 3 was identified as the major route of metabolism in the cynomolgus monkey. Modification of the template to give the cinnoline 9 retained potency and selectivity, and greatly improved the pharmacokinetic profile in the cynomolgus monkey compared with 1. Additional SAR studies aimed at improving the solubility of 9 are also described., (Copyright 2009 Elsevier Ltd. All rights reserved.)

A series of tetrahydroquinoline-derived inhibitors of the CRTH2 receptor was discovered by a high throughput screen. Optimization of these compounds for potency and pharmacokinetic properties led to the discovery of potent and orally bioavailable CRTH2 antagonists.

Crystallography driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of quinoline-3-carboxamides as highly potent and selective inhibitors of phosphodiesterase 4B. This series has been optimized to GSK256066, a potent PDE4B inhibitor which also inhibits LPS induced production of TNF-alpha from isolated human peripheral blood mononuclear cells with a pIC(50) of 11.1. GSK256066 also has a suitable profile for inhaled dosing.

Substituted 8-arylquinoline analogs bearing alkyl-linked side chain were identified as potent inhibitors of type 4 phophodiesterase. These compounds address the potential liabilities of the clinical candidate L-454560. The pharmacokinetic profile of the best analogs and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.

Tpl2 (cot/MAP3K8) is an upstream kinase of MEK in the ERK pathway. It plays an important role in Tumor Necrosis Factor-alpha (TNF-alpha) production and signaling. We have discovered that 8-halo-4-(3-chloro-4-fluoro-phenylamino)-6-[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-quinoline-3-carbonitriles (4) are potent inhibitors of this enzyme. In order to improve the inhibition of TNF-alpha production in LPS-stimulated human blood, a series of analogs with a variety of substitutions around the triazole moiety were studied. We found that a cyclic amine group appended to the triazole ring could considerably enhance potency, aqueous solubility, and cell membrane permeability. Optimization of these cyclic amine groups led to the identification of 8-chloro-4-(3-chloro-4-fluorophenylamino)-6-((1-(1-ethylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)methylamino)quinoline-3-carbonitrile (34). In a LPS-stimulated rat inflammation model, compound 34 showed good efficacy in inhibiting TNF-alpha production.

A new series of benzothiazine-substituted quinolinediones were evaluated as inhibitors of HCV polymerase NS5B. SAR studies on this series revealed a methyl sulfonamide group as a high affinity feature. Analogues with this group showed submicromolar potencies in the HCV cell based replicon assay. Pharmacokinetic and toxicology studies were also performed on a selected compound (34) to evaluate in vivo properties of this new class of inhibitors of HCV NS5B polymerase.

3-amido-4-anilinoquinolines are potent and highly selective inhibitors of CSF-1R. Their synthesis and SAR is reported, along with initial efforts to optimize the physical properties and PK through modifications at the quinoline 6- and 7-positions.

The optimization of compounds from the 3-amido-4-anilinoquinolines series of CSF-1R kinase inhibitors is described. The series has excellent activity and kinase selectivity. Excellent physical properties and rodent PK profiles were achieved through the introduction of cyclic amines at the quinoline 6-position. Compounds with good activity in a mouse PD model measuring inhibition of pCSF-1R were identified.

A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different in vitro pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.

A new series of EP(4) antagonists based on a quinoline acylsulfonamide scaffold have been identified as part of our on-going efforts to develop treatments for chronic inflammation. These compounds show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. Acceptable pharmacokinetic profiles have also been demonstrated across a series of preclinical species.

The structure-activity relationship of a novel series of 8-biarylquinolines acting as type 4 phosphodiesterase (PDE4) inhibitors is described herein. Prototypical compounds from this series are potent and non-selective inhibitors of the four distinct PDE4 (IC(50)<10 nM) isozymes (A-D). In a human whole blood in vitro assay, they inhibit (IC(50)<0.5 microM) the LPS-induced release of the cytokine TNF-alpha. Optimized inhibitors were evaluated in vivo for efficacy in an ovalbumin-induced bronchoconstriction model in conscious guinea pigs. Their propensity to produce an emetic response was evaluated by performing pharmacokinetic studies in squirrel monkeys. This work has led to the identification of several compounds with excellent in vitro and in vivo profiles, including a good therapeutic window of efficacy over emesis.

The synthesis and biological evaluation of a novel series of 2-aminoquinoline substituted piperidines and tropanes incorporating a homotropene moiety is herein described. The series exhibits potent antagonism of the CXCR3 receptor and superior physicochemical properties. Compound 24d was found to be orally bioavailable, and PK/PD studies suggested it as a suitable tool for studying the role of CXCR3 in models of disease.

The radiosynthesis and the radiopharmacological characterization of [(11)C]AL-438 as a nonsteroidal ligand for the glucocorticoid receptor (GR) is described. Radiolabeling of the corresponding desmethyl precursor 10 with [(11)C]MeI gave [(11)C]AL-438 in decay-corrected radiochemical yields of 30+/-4% (based upon [(11)C]CO(2)) within 35 min at a specific radioactivity of 10-15 GBq/micromol at the end-of-synthesis. The radiopharmacological evaluation of [(11)C]AL-438 involved biodistribution and small animal PET imaging in rats, and autoradiography studies using rat brain sections. Biodistribution studies were performed in male Wistar rats and demonstrated high radioactivity uptake in pituitary and brain. However, the inability of high dose corticosterone to block binding would suggest that the radioactivity accumulation in the brain was not receptor-mediated.

Potent inhibitors of the human PDE IV enzyme are described. Substituted 8-arylquinoline analogs bearing nitrogen-linked side chain were identified as potent inhibitors based on the SAR described herein. The pharmacokinetic profile of the best analog and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.

Indole-3-carbinol (I3C), a compound found in cruciferous vegetables, inhibits the formation of DNA adducts, colonic aberrant crypts, and tumors in rats given heterocyclic amines, such as 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). Previous mechanism studies indicated that I3C induces cytochromes P4501A1 (CYP1A1) and CYP1A2, as well as phase 2 pathways, leading to enhanced metabolism and excretion of IQ. However, the chemopreventive activity is dependent on the dose of I3C, and at low doses which do not induce CYP1A activity, there is evidence for increased IQ-DNA adduct formation in vivo. The present study examined the fate of IQ in the rat and the profile of urinary metabolites across a broad range of I3C doses. Male F344 rats were given a single injection of I3C by oral gavage, at a dose equivalent to that received from a single daily exposure to 0, 5, 10, 25, 50, 100, 200, 500 or 1000 ppm I3C in the diet, or they were given the 1000-ppm-equivalent dose of I3C for 14 consecutive days. Subsequently, each rat was given 14C-labeled IQ (5 mg/kg; 0.1 mCi/kg) and the animal was sacrificed 8 h later. With increasing I3C, there was a dose-dependent decrease in IQ-associated radiolabel in several systemic tissues, and an increase in the radiolabel eliminated via the feces. In the urine, there was a dose-dependent increase in IQ-5-O-glucuronide and IQ-5-O-sulfate metabolites, and a concomitant decrease in the IQ-sulfamate at intermediate and high doses of I3C. However, 5- and 10 ppm-equivalent doses of I3C enhanced the levels of IQ-sulfamate compared with controls, possibly due to the high ratio of hepatic CYP1A2 versus CYP1A1 activities at these I3C doses. The possible significance of the low versus high dose effects are discussed in the context of ongoing clinical trials with I3C and the reported chemopreventive mechanisms in vivo.

It has commonly been believed that increasing fibre in the diet should reduce the incidence of cancers, especially those of the colon and rectum. The earliest definitions of dietary fibre restricted the term to plant cell walls in which non-starch polysaccharides are key chemical components. However, new definitions encompass a wider range of materials, including starches resistant to digestion in the colon (resistant starches). Nevertheless, most definitions require that "dietary fibres" show physiological effects considered beneficial against cancer, including enhanced laxation and faecal bulking. On theoretical grounds, such properties might be expected to dilute the concentration of any carcinogen present and move it more rapidly through the colon, thereby reducing bioavailability. We have compared the properties of two dietary fibre preparations that are primarily non-starch polysaccharides with two resistant starch preparations for effects on carcinogen disposition in a rodent model. Although both preparations enhanced laxation and faecal bulking, only the non-starch polysaccharide preparation reduced carcinogen biovailability. Indeed, carcinogen biovailability was significantly enhanced by resistant starch. We suggest that there may be fundamental differences in the manner by which non-starch polysaccharides or resistant starches affect carcinogen disposition, and express concern that the events seen with the resistant starches [RS] are unlikely to be beneficial with respect to protection against cancer by exogenous carcinogens. Furthermore, the data reveal that the observation of enhanced laxation and faecal bulking does not necessarily imply a reduction in carcinogen bioavailability.

A series of quinoline-3-carbothioamides and their analogues was prepared via four synthetic routes and evaluated for their antinephritic and immunomodulating activities. The optimal compound 9g strongly inhibited the T-cell independent antibody production in mice immunized with TNP-LPS and was highly effective in two nephritis models, namely chronic graft-versus-host disease and autoimmune MRL/l mice.

The syntheses and pharmacological profiles of some 2-trifluoromethyl-8-methoxyquinoline-5-carboxamides are described. SCH351591 is a potent selective inhibitor of phosphodiesterase type 4 (PDE4).

The synthesis and pharmacological profile of a novel series of 2-substituted 8-methoxyquinolines is described. The 2-trifluoromethyl compound was found to be a potent inhibitor of phosphodiesterase type 4 (PDE4).

Recently, a study of docetaxel in combination with the new orally administered P-glycoprotein (P-gp) inhibitor R101933 showed that this combination was feasible. However, due to the low oral bioavailability of R101933 and high interpatient variability, no further attempts to increase the level of P-gp inhibition were made. Here, we assessed the feasibility of combining docetaxel with intravenously (i.v.) administered R101933, and determined the disposition of docetaxel with and without the P-gp inhibitor. Patients received i.v. R101933 alone at a dose escalated from 250 to 500 mg on day 1 (cycle 0), docetaxel 100 mg/m(2) as a 1-h infusion on day 8 (cycle 1) and the combination every 3 weeks thereafter (cycle 2 and further cycles). 12 patients were entered into the study, of whom 9 received the combination treatment. Single treatment with i.v. R101933 was associated with minimal toxicity consisting of temporary drowsiness and somnolence. Dose-limiting toxicity consisting of neutropenic fever was seen in cycles 1 and 2 or in further cycles at both dose levels. The plasma pharmacokinetics of docetaxel were not changed by the R101933 regimen at any dose level tested, as indicated by plasma clearance values of 22.5+/-6.2 l/h/m(2) and 24.2+/-7.4 l/h/m(2) (P=0.38) in cycles 1 and 2, respectively. However, the faecal excretion of unchanged docetaxel decreased significantly after the combination treatment from 2.5+/-2.1% to less than 1% of the administered dose of docetaxel, most likely due to inhibition of the intestinal P-gp by R101933. Plasma concentrations of R101933 were not different in cycles 0 or 2 and the concentrations achieved in the first 12-h period after i.v. infusion were capable of inhibiting P-gp in an ex vivo assay. We conclude that the combination of 100 mg/m(2) i.v. docetaxel and 500 mg i.v. R101933 is feasible, lacks pharmacokinetic interaction in plasma, and shows evidence of P-gp inhibition both in an ex vivo assay and in vivo as indicated by the inhibition of intestinal P-gp.

We synthesized the glucuronides of MS-209 to identify the two main unknown metabolites in human urine. Reaction of MS-209 and glucuronyl trichloroacetimidate gave two beta-isomers, which were each glucuronate of (R)- and (S)-MS-209. These spectrum data were identical with the metabolites.