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Biomedical subjects

Kennan Marsh

Publications and source records attributed to Kennan Marsh.

At least 19 recordsLinked to original sources
PubMed2006

Plasma and cerebrospinal fluid pharmacokinetics of intravenously administered ABT-751 in non-human primates.

PURPOSE: ABT-751 is an orally bioavailable sulfonamide that binds to the colchicine binding site on beta-tubulin and inhibits microtubule polymerization. The plasma and cerebrospinal fluid (CSF) pharmacokinetics of ABT-751, after a short intravenous infusion, were evaluated in a non-human primate (Macaca mulatta) model that is highly predictive of the CSF penetration of drugs in humans. MATERIALS AND METHODS: Plasma and CSF samples were collected over 24 h after 7.5 mg/kg (150 mg/m2) ABT-751 infused over 0.25-0.70 h, and ABT-751 concentrations in plasma and CSF were quantified using a validated HPLC-MS/MS assay. Pharmacokinetic parameters in plasma and CSF were derived using non-compartmental methods. RESULTS AND CONCLUSION: Plasma disappearance was bi-exponential with a terminal half-life of 13 h. The mean +/- SD clearance was 100 +/- 18 ml/min m2, the mean +/- SD volume of distribution at steady state was 1.3 +/- 0.5 l/kg, and the mean +/- SD mean residence time was 4.6 +/- 1.8 h. The mean +/- SD peak ABT-751 concentration in CSF was 0.26 +/- 0.08 microM, and the mean +/- SD CSF half-life of 1.3 +/- 0.3 h. CSF penetration was limited (mean +/- SD AUC(CSF):AUC(plasma), 1.1 +/- 0.3%) relative to total (protein-bound + free) plasma drug concentrations, but the CSF concentrations approximated the estimated free drug concentrations in plasma.

Animals↗
PubMed2006

A-740003 [N-(1-{[(cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a novel and selective P2X7 receptor antagonist, dose-dependently reduces neuropathic pain in the rat.

ATP-sensitive P2X(7) receptors are localized on cells of immunological origin including glial cells in the central nervous system. Activation of P2X(7) receptors leads to rapid changes in intracellular calcium concentrations, release of the proinflammatory cytokine interleukin-1beta (IL-1beta), and following prolonged agonist exposure, cytolytic plasma membrane pore formation. P2X(7) knockout mice show reduced inflammation as well as decreased nociceptive sensitivity following peripheral nerve injury. A-740003 (N-(1-{[(cyanoimino)(5-quinolinylamino) methyl] amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide) is a novel competitive antagonist of P2X(7) receptors (IC(50) values = 40 nM for human and 18 nM for rat) as measured by agonist-stimulated changes in intracellular calcium concentrations. A-740003 showed weak or no activity (IC(50) > 10 muM) at other P2 receptors and an array of other neurotransmitter and peptide receptors, ion channels, reuptake sites, and enzymes. A-740003 potently blocked agonist-evoked IL-1beta release (IC(50) = 156 nM) and pore formation (IC(50) = 92 nM) in differentiated human THP-1 cells. Systemic administration of A-740003 produced dose-dependent antinociception in a spinal nerve ligation model (ED(50) = 19 mg/kg i.p.) in the rat. A-740003 also attenuated tactile allodynia in two other models of neuropathic pain, chronic constriction injury of the sciatic nerve and vincristine-induced neuropathy. In addition, A-740003 effectively reduced thermal hyperalgesia observed following intraplantar administration of carrageenan or complete Freund's adjuvant (ED(50) = 38-54 mg/kg i.p.). A-740003 was ineffective in attenuating acute thermal nociception in normal rats and did not alter motor performance at analgesic doses. These data demonstrate that selective blockade of P2X(7) receptors in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.

Acetamides↗
PubMed2006

A small-molecule inhibitor of Bcl-XL potentiates the activity of cytotoxic drugs in vitro and in vivo.

Inhibition of the prosurvival members of the Bcl-2 family of proteins represents an attractive strategy for the treatment of cancer. We have previously reported the activity of ABT-737, a potent inhibitor of Bcl-2, Bcl-X(L), and Bcl-w, which exhibits monotherapy efficacy in xenograft models of small-cell lung cancer and lymphoma and potentiates the activity of numerous cytotoxic agents. Here we describe the biological activity of A-385358, a small molecule with relative selectivity for binding to Bcl-X(L) versus Bcl-2 (K(i)'s of 0.80 and 67 nmol/L for Bcl-X(L) and Bcl-2, respectively). This compound efficiently enters cells and co-localizes with the mitochondrial membrane. Although A-385358 shows relatively modest single-agent cytotoxic activity against most tumor cell lines, it has an EC(50) of <500 nmol/L in cells dependent on Bcl-X(L) for survival. In addition, A-385358 enhances the in vitro cytotoxic activity of numerous chemotherapeutic agents (paclitaxel, etoposide, cisplatin, and doxorubicin) in several tumor cell lines. In A549 non-small-cell lung cancer cells, A-385358 potentiates the activity of paclitaxel by as much as 25-fold. Importantly, A-385358 also potentiated the activity of paclitaxel in vivo. Significant inhibition of tumor growth was observed when A-385358 was added to maximally tolerated or half maximally tolerated doses of paclitaxel in the A549 xenograft model. In tumors, the combination therapy also resulted in a significant increase in mitotic arrest followed by apoptosis relative to paclitaxel monotherapy.

Aniline Compounds↗
PubMed2006

Identification of a novel 3,5-disubstituted pyridine as a potent, selective, and orally active inhibitor of Akt1 kinase.

Based on lead compounds 2 and 3 a series of 3,5-disubstituted pyridines have been designed and evaluated for inhibition of AKT/PKB. Modifications at the 3 position of the pyridine ring led to a number of potent compounds with improved physical properties, resulting in the identification of 11g as a promising, orally active Akt inhibitor. The synthesis, structure-activity relationship studies, and pharmacokinetic data are presented in this paper.

3-Phosphoinositide-Dependent Protein Kinases↗
PubMed2006

Discovery and structure-activity relationship of antagonists of B-cell lymphoma 2 family proteins with chemopotentiation activity in vitro and in vivo.

Development of a rationally designed potentiator of cancer chemotherapy, via inhibition of Bcl-X(L) function, is described. Lead compounds generated by NMR screening and directed parallel synthesis displayed sub-microM binding but were strongly deactivated in the presence of serum. The dominant component of serum deactivation was identified as domain III of human serum albumin (HSA); NMR solution structures of inhibitors bound to both Bcl-X(L) and HSA domain III indicated two potential optimization sites for separation of affinities. Modifications at both sites resulted in compounds with improved Bcl-X(L) binding and greatly increased activity in the presence of human serum, culminating in 73R, which bound to Bcl-X(L) with a K(i) of 0.8 nM. In a cellular assay 73R reversed the protection afforded by Bcl-X(L) overexpression against cytokine deprivation in FL5.12 cells with an EC(50) of 0.47 microM. 73R showed little effect on the viability of the human non small cell lung cancer cell line A549. However, consistent with the proposed mechanism, 73R potentiated the activity of paclitaxel and UV irradiation in vitro and potentiated the antitumor efficacy of paclitaxel in a mouse xenograft model.

Aniline Compounds↗
PubMed2006

Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome.

AMP-activated protein kinase (AMPK) is a key sensor and regulator of intracellular and whole-body energy metabolism. We have identified a thienopyridone family of AMPK activators. A-769662 directly stimulated partially purified rat liver AMPK (EC50 = 0.8 microM) and inhibited fatty acid synthesis in primary rat hepatocytes (IC50 = 3.2 microM). Short-term treatment of normal Sprague Dawley rats with A-769662 decreased liver malonyl CoA levels and the respiratory exchange ratio, VCO2/VO2, indicating an increased rate of whole-body fatty acid oxidation. Treatment of ob/ob mice with 30 mg/kg b.i.d. A-769662 decreased hepatic expression of PEPCK, G6Pase, and FAS, lowered plasma glucose by 40%, reduced body weight gain and significantly decreased both plasma and liver triglyceride levels. These results demonstrate that small molecule-mediated activation of AMPK in vivo is feasible and represents a promising approach for the treatment of type 2 diabetes and the metabolic syndrome.

AMP-Activated Protein Kinases↗
PubMed2006

Practical preclinical model for assessing the potential for unconjugated hyperbilirubinemia produced by human immunodeficiency virus protease inhibitors.

A practical preclinical model for the hyperbilirubinemia produced by human immunodeficiency virus protease inhibitors has been developed. Indinavir and atazanavir produced significant hyperbilirubinemia, whereas amprenavir, the negative control, was indistinguishable from the ritonavir booster dose. This model was used to disqualify an exploratory protease inhibitor from development.

Animals↗
PubMed2005

Synthesis and SAR of 5-amino- and 5-(aminomethyl)benzofuran histamine H3 receptor antagonists with improved potency.

A new series of H3 receptor antagonists was discovered with nanomolar and subnanomolar affinities at human and rat H3 receptors. Starting from an earlier, more structurally limited series of benzofurans, the present series of compounds demonstrated increased structural variety and flexibility with greater in vitro potency. One compound in particular, [2-[2-(2-(R)-methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl](5-nitropyridin-2-yl)amine (7h), gave the best binding potency (human K(i) of 0.05 nM, rat K(i) of 0.11 nM), which represented a 9-fold (in human) and an 11-fold (in rat) improvement over ABT-239 (compound 5), a compound previously reported to have excellent in vitro potency and in vivo efficacy. The synthesis, SAR of the H3 binding affinities, in vitro assay for phospholipidosis, and pharmacokinetic properties of the new compounds are described.

Animals↗
PubMed2005

Rapamycin analogs with reduced systemic exposure.

The synthesis and biological activities of rapamycin (I) analogs modified at the C-40 position are reported. Emphasis placed on compounds that potentially have an improved safety profile on account of their shorter in vivo half-life when compared with rapamycin.

Animals↗
PubMed2005

Discovery and characterization of aminopiperidinecoumarin melanin concentrating hormone receptor 1 antagonists.

4-(1-Benzo[1,3]dioxol-5-ylmethylpiperidine-4-ylmethyl)-6-chlorochromen-2-one (7) is a potent, orally bioavailable melanin concentrating hormone receptor 1 (MCHr1) antagonist that causes dose-dependent weight loss in diet-induced obese mice. Further evaluation of 7 in an anesthetized dog model of cardiovascular safety revealed adverse hemodynamic effects at a plasma concentration comparable to the minimally effective therapeutic concentration. These results highlight the need for scrutiny of the cardiovascular safety profile of MCHr1 antagonists.

Administration, Oral↗
PubMed2005

A-412997 is a selective dopamine D4 receptor agonist in rats.

A-412997 (2-(3',4',5',6'-tetrahydro-2'H-[2,4'] bipyridinyl-1'-yl)-N-m-tolyl-acetamide) is a highly selective dopamine D4 receptor agonist that binds with high affinity to rat dopamine D4 and human dopamine D4.4 receptors (Ki=12.1 and 7.9 nM, respectively). In contrast to the dopamine D4 receptor agonists PD168077 and CP226269, A-412997 showed a better selectivity profile and no affinity <1000 nM for other dopamine receptors or any other proteins in a panel of seventy different receptors and channels. In functional assays using calcium flux, A-412997 was a potent full agonist at rat dopamine D4 receptors (28.4 nM, intrinsic activity=0.83) and did not activate rat dopamine D2L receptors, unlike CP226269. Dopamine D4 receptor selective agonists have been shown to induce penile erection in rats by central mechanisms. A-412997 induces penile erection in a conscious rat model (effective dose=0.1 micromol/kg, s.c.) with comparable efficacy as the nonselective D2-like agonist, apomorphine. When dosed systemically, A-412997 crossed the blood brain barrier rapidly and achieved significantly higher levels than PD168077. A-412997 is a highly selective dopamine D4 receptor agonist and a useful tool to understand the role of dopamine D4 receptors in rat models of central nervous system processes and disease.

Acetamides↗
PubMed2005

A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea], a novel transient receptor potential type V1 receptor antagonist, relieves pathophysiological pain associated with inflammation and tissue injury in rats.

The vanilloid receptor 1 (VR1, TRPV1), which is a member of the transient receptor potential (TRP) superfamily, is highly localized on peripheral and central processes of nociceptive afferent fibers. Activation of TRPV1 contributes to the pronociceptive effects of capsaicin, protons, heat, and various endogenous lipid agonists such as anandamide and N-arachidonoyl-dopamine. A-425619 [1-isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)urea] is a novel potent and selective antagonist at both human and rat TRPV1 receptors. In vivo, A-425619 dose dependently reduced capsaicin-induced mechanical hyperalgesia (ED50 = 45 micromol/kg p.o.). A-425619 was also effective in models of inflammatory pain and postoperative pain. A-425619 potently reduced complete Freund's adjuvant-induced chronic inflammatory pain after oral administration (ED50 = 40 micromol/kg p.o.) and was also effective after either i.t. administration or local injection into the inflamed paw. Furthermore, A-425619 maintained efficacy in the postoperative pain model after twice daily dosing p.o. for 5 days. A-425619 also showed partial efficacy in models of neuropathic pain. A-425619 did not alter motor performance at the highest dose tested (300 micromol/kg p.o.). Taken together, the present data indicate that A-425619, a potent and selective antagonist of TRPV1 receptors, effectively relieves acute and chronic inflammatory pain and postoperative pain.

Acute Disease↗
PubMed2005

Antitumor activity of orally bioavailable farnesyltransferase inhibitor, ABT-100, is mediated by antiproliferative, proapoptotic, and antiangiogenic effects in xenograft models.

PURPOSE: To evaluate the preclinical pharmacokinetics, antitumor efficacy, and mechanism of action of a novel orally active farnesyltransferase inhibitor, ABT-100. EXPERIMENTAL DESIGN: In vitro sensitivity of a panel of human cell lines was determined using proliferation and clonogenic assays. In vivo efficacy of ABT-100 was evaluated in xenograft models (flank or orthotopic) by assessing angiogenesis, proliferation, and apoptosis in correlation with pharmacokinetics. Efficacy of the racemate of ABT-100 (A-367074) was also compared with R115777 (tipifarnib). RESULTS: ABT-100 inhibited proliferation of cells in vitro carrying oncogenic H-Ras (EJ-1 bladder; IC(50) 2.2 nmol/L), Ki-Ras (DLD-1 colon, MDA-MB-231 breast, HCT-116 colon, and MiaPaCa-2 pancreatic; IC(50) range, 3.8-9.2 nmol/L), and wild-type Ras (PC-3 and DU-145; IC(50), 70 and 818 nmol/L, respectively) as well as clonogenic potential. ABT-100 shows 70% to 80% oral bioavailability in mice. ABT-100 regressed EJ-1 tumors (2-12.5 mg/kg/d s.c., every day for 21 days) and showed significant efficacy in DLD-1, LX-1, MiaPaCa-2, or PC-3 tumor-bearing mice (6.25-50 mg/kg/d s.c. once daily or twice daily orally). A-367074 showed equivalent efficacy to R115777 given at approximately one-fourth the total dose of R115777 for a shorter duration (EJ-1 and LX-1). Antitumor activity was associated with decreased cell proliferation (Ki-67), increased apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling), and decreased angiogenesis. A reduction in tumor angiogenic cytokine levels (vascular endothelial growth factor, basic fibroblast growth factor, and interleukin-8) correlated with a reduction in tumor vascularity (CD31). CONCLUSIONS: Overall, ABT-100 has an acceptable pharmacokinetic profile, is well tolerated, and possesses broad-spectrum antitumor activity against a series of xenograft models similar to farnesyltransferase inhibitors in clinical development; therefore, it is an attractive candidate for clinical evaluation.

Administration, Oral↗
PubMed2005

2-[4-(3,4-Dimethylphenyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393), a selective dopamine D4 receptor antagonist.

2-[4-(3,4-Dimethylphenlyl)piperazin-1-ylmethyl]-1H benzoimidazole (A-381393) was identified as a potent dopamine D4 receptor antagonist with excellent receptor selectivity. [3H]-spiperone competition binding assays showed that A-381393 potently bound to membrane from cells expressing recombinant human dopamine D4.4 receptor (Ki=1.5 nM), which was 20-fold higher than that of clozapine (Ki=30.4 nM). A-381393 exhibited highly selective binding for the dopamine D4.4 receptor (>2700-fold) when compared to D1, D2, D3 and D5 dopamine receptors. Furthermore, in comparison to clozapine and L-745870, A-381393 exhibits better receptor selectivity, showing no affinity up to 10 microM for a panel of more than 70 receptors and channels, with the exception of moderate affinity for 5-HT2A (Ki=370 nM). A-381393 potently inhibited the functional activity of agonist-induced GTP-gamma-S binding assay and 1 microM dopamine induced-Ca2+ flux in human dopamine D4.4 receptor expressing cells, but not in human dopamine D2L or D3 receptor cells. In contrast to L-745870, A-381393 did not exhibit any significant intrinsic activity in a D4.4 receptor. In vivo, A-381393 has good brain penetration after subcutaneous administration. A-381393 inhibited penile erection induced by the selective D4 agonist PD168077 in conscious rats. Thus, A-381393 is a novel selective D4 antagonist that will enhance the ability to study dopamine D4 receptors both in vitro and in vivo.

Animals↗
PubMed2005

Hepatic glucocorticoid receptor antagonism is sufficient to reduce elevated hepatic glucose output and improve glucose control in animal models of type 2 diabetes.

Glucocorticoids amplify endogenous glucose production in type 2 diabetes by increasing hepatic glucose output. Systemic glucocorticoid blockade lowers glucose levels in type 2 diabetes, but with several adverse consequences. It has been proposed, but never demonstrated, that a liver-selective glucocorticoid receptor antagonist (LSGRA) would be sufficient to reduce hepatic glucose output (HGO) and restore glucose control to type 2 diabetic patients with minimal systemic side effects. A-348441 [(3b,5b,7a,12a)-7,12-dihydroxy-3-{2-[{4-[(11b,17b)-17-hydroxy-3-oxo-17-prop-1-ynylestra-4,9-dien-11-yl] phenyl}(methyl)amino]ethoxy}cholan-24-oic acid] represents the first LSGRA with significant antidiabetic activity. A-348441 antagonizes glucocorticoid-up-regulated hepatic genes, normalizes postprandial glucose in diabetic mice, and demonstrates synergistic effects on blood glucose in these animals when coadministered with an insulin sensitizer. In insulin-resistant Zucker fa/fa rats and fasted conscious normal dogs, A-348441 reduces HGO with no acute effect on peripheral glucose uptake. A-348441 has no effect on the hypothalamic pituitary adrenal axis or on other measured glucocorticoid-induced extrahepatic responses. Overall, A-348441 demonstrates that an LSGRA is sufficient to reduce elevated HGO and normalize blood glucose and may provide a new therapeutic approach for the treatment of type 2 diabetes.

3T3 Cells↗
PubMed2005

A highly potent and selective farnesyltransferase inhibitor ABT-100 in preclinical studies.

Ras mutation has been detected in approximately 20-30% of all human carcinomas, primarily in pancreatic, colorectal, lung and bladder carcinomas. The indirect inhibition of Ras activity by inhibiting farnesyltransferase (FTase) function is one therapeutic intervention to control tumor growth. Here we report the preclinical anti-tumor activity of our most advanced FTase inhibitor (FTI), ABT-100, and a direct comparison with the current clinical candidates. ABT-100 is a highly selective, potent and orally bioavailable FTI. It broadly inhibits the growth of solid tumors in preclinical animal models. Thus, ABT-100 is an attractive candidate for further clinical evaluation. In addition, our results provide plausible insights to explain the impressive potency and selectivity of ABT-100. Finally, we have demonstrated that ABT-100 significantly suppresses the expression of vascular endothelial growth factor (VEGF) mRNA and secretion of VEGF protein, as well as inhibiting angiogenesis in the animal model.

Animals↗
PubMed2004

Pharmacological properties of ABT-239 [4-(2-{2-[(2R)-2-Methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile]: I. Potent and selective histamine H3 receptor antagonist with drug-like properties.

Histamine H3 receptor antagonists are being developed to treat a variety of neurological and cognitive disorders that may be ameliorated by enhancement of central neurotransmitter release. Here, we present the in vitro pharmacological and in vivo pharmacokinetic profiles for the nonimidazole, benzofuran ligand ABT-239 [4-(2-{2-[(2R)-2-methylpyrrolidinyl]ethyl}-benzofuran-5-yl)benzonitrile] and compare it with several previously described imidazole and nonimidazole H3 receptor antagonists. ABT-239 binds to recombinant human and rat H3 receptors with high affinity, with pK(i) values of 9.4 and 8.9, respectively, and is over 1000-fold selective versus human H1, H2, and H4 histamine receptors. ABT-239 is a potent H3 receptor antagonist at recombinant human and rat receptors, reversing agonist-induced changes in cAMP formation (pK(b) = 7.9 and 7.6, respectively), guanosine 5'-O-(3-[35S]thio) triphosphate ([35S]GTPgammaS) binding (pK(b) = 9.0 and 8.3, respectively), and calcium mobilization (human pK(b) = 7.9). ABT-239 also competitively reversed histamine-mediated inhibition of [3H]histamine release from rat brain cortical synaptosomes (pK(b) = 7.7) and agonist-induced inhibition of contractile responses in electric field stimulated guinea pig ileal segments (pA2 = 8.7). Additionally, ABT-239 is a potent inverse agonist, inhibiting constitutive [35S]GTPgammaS binding at both rat and human H3 receptors with respective pEC50 values of 8.9 and 8.2. ABT-239 demonstrates good pharmacokinetic characteristics in rat, dog, and monkey with t1/2 values ranging from 4 to 29 h, corresponding with clearance values and metabolic turnover in liver microsomes from these species, and good oral bioavailability ranging from 52 to 89%. Thus, ABT-239 is a selective, nonimidazole H3 receptor antagonist/inverse agonist with similar high potency in both human and rat and favorable drug-like properties.

Adenylyl Cyclases↗