David W A Beno

Publications (21)91.07 Total impact

• Article: Identification and preliminary characterization of a potent, safe, and orally efficacious inhibitor of acyl-CoA:diacylglycerol acyltransferase 1.

  Vince S C Yeh, David W A Beno, Sevan Brodjian, Michael E Brune, Steven C Cullen, Brian D Dayton, Madhup K Dhaon, Hugh D Falls, Ju Gao, Nelson Grihalde, [......], Eric J Stoner, Martin J Voorbach, Xiaojun Wang, Xili Xin, Gang Zhao, Christine A Collins, Bryan F Cox, Regina M Reilly, Philip R Kym, Andrew J Souers
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  ABSTRACT: A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective, and orally bioavailable compound 14. Oral administration at doses ≥0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. Further assessment in both acute and chronic safety pharmacology and toxicology studies demonstrated a clean profile up to high plasma levels, thus culminating in the nomination of 14 as clinical candidate ABT-046.
  Journal of Medicinal Chemistry 02/2012; 55(4):1751-7. · 4.80 Impact Factor
• Article: Hepatitis C NS5B polymerase inhibitors: functional equivalents for the benzothiadiazine moiety.

  Douglas K Hutchinson, Charles A Flentge, Pamela L Donner, Rolf Wagner, Clarence J Maring, Warren M Kati, Yaya Liu, Sherie V Masse, Tim Middleton, Hongmei Mo, Debra Montgomery, Wen W Jiang, Gennadiy Koev, David W A Beno, Kent D Stewart, Vincent S Stoll, Akhteruzzaman Molla, Dale J Kempf
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  ABSTRACT: A series of quinoline derivatives was synthesized as potential bioisosteric replacements for the benzothiadiazine moiety of earlier Hepatitis C NS5B polymerase inhibitors. Several of these compounds exhibited potent activity in enzymatic and replicon assays.
  Bioorganic & medicinal chemistry letters 01/2011; 21(6):1876-9. · 2.65 Impact Factor
• Article: Synthesis and biological characterization of B-ring amino analogues of potent benzothiadiazine hepatitis C virus polymerase inhibitors.

  John T Randolph, Charles A Flentge, Peggy P Huang, Douglas K Hutchinson, Larry L Klein, Hock B Lim, Rubina Mondal, Thomas Reisch, Debra A Montgomery, Wen W Jiang, Sherie V Masse, Lisa E Hernandez, Rodger F Henry, Yaya Liu, Gennadiy Koev, Warren M Kati, Kent D Stewart, David W A Beno, Akhteruzzaman Molla, Dale J Kempf
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  ABSTRACT: Benzothiadiazine inhibitors of the HCV NS5B RNA-dependent RNA polymerase are an important class of non-nucleoside inhibitors that have received considerable attention in the search for novel HCV therapeutics. Research in our laboratories has identified a novel series of tetracyclic benzothiadiazine inhibitors of HCV polymerase bearing a benzylamino substituent on the B-ring. Compounds in this series exhibit low-nanomolar activities in both genotypes 1a and 1b polymerase inhibition assays and subgenomic replicon assays. Optimization of pharmacokinetic properties in rat led to compound 30, which has good oral bioavailability (F = 56%) and a favorable tissue distribution drug profile, with high liver to plasma ratios. Compound 30 is a potent inhibitor in replicon assays, with EC(50) values of 10 and 6 nM against genotypes 1a and 1b, respectively.
  Journal of Medicinal Chemistry 05/2009; 52(10):3174-83. · 4.80 Impact Factor
• Article: Inhibitors of hepatitis C virus polymerase: synthesis and biological characterization of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines.

  Rolf Wagner, Daniel P Larson, David W A Beno, Todd D Bosse, John F Darbyshire, Yi Gao, Bradley D Gates, Wenping He, Rodger F Henry, Lisa E Hernandez, [......], Yaya Liu, Michelle A Long, Clarence J Maring, Sherie V Masse, Tim Middleton, Debra A Montgomery, John K Pratt, Patricia Stuart, Akhteruzzaman Molla, Dale J Kempf
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  ABSTRACT: The hepatitis C virus (HCV) NS5B polymerase is essential for viral replication and has been a prime target for drug discovery research. Our efforts directed toward the discovery of HCV polymerase inhibitors resulted in the identification of unsymmetrical dialkyl-hydroxynaphthalenoyl-benzothiadiazines 2 and 3. The most active compound displayed activity in genotypes 1a and 1b polymerase and replicon cell culture inhibition assays at subnanomolar and low nanomolar concentrations, respectively. It also displayed an excellent pharmacokinetic profile in rats, with a plasma elimination half-life after intravenous dosing of 4.5 h, oral bioavailability of 77%, and a peak liver concentration of 21.8 microg/mL.
  Journal of Medicinal Chemistry 03/2009; 52(6):1659-69. · 4.80 Impact Factor
• Article: Hepatitis C NS5B polymerase inhibitors: 4,4-Dialkyl-1-hydroxy-3-oxo-3,4-dihydronaphthalene-3-yl benzothiadiazine derivatives.

  Douglas K Hutchinson, Teresa Rosenberg, Larry L Klein, Todd D Bosse, Daniel P Larson, Wenping He, Wen W Jiang, Warren M Kati, William E Kohlbrenner, Yaya Liu, Sherie V Masse, Tim Middleton, Akhteruzzaman Molla, Debra A Montgomery, David W A Beno, Kent D Stewart, Vincent S Stoll, Dale J Kempf
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  ABSTRACT: 4,4-Dialkyl-1-hydroxy-3-oxo-3.4-dihydronaphthalene-3-yl benzothiadiazine derivatives were synthesized and evaluated as inhibitors of genotypes 1a and 1b HCV NS5B polymerase. A number of these compounds exhibited potent activity against genotypes 1a and 1b HCV polymerase in both enzymatic and cell culture activities. A representative compound also showed favorable pharmacokinetics in the rat.
  Bioorganic & medicinal chemistry letters 08/2008; 18(14):3887-90. · 2.65 Impact Factor
• Article: Validation of diacyl glycerolacyltransferase I as a novel target for the treatment of obesity and dyslipidemia using a potent and selective small molecule inhibitor.

  Gang Zhao, Andrew J Souers, Martin Voorbach, H Doug Falls, Brian Droz, Sevan Brodjian, Yau Yi Lau, Rajesh R Iyengar, Ju Gao, Andrew S Judd, [......], Dennis Fry, David W A Beno, Kennan C Marsh, Zhi Su, Gilbert J Diaz, Christine A Collins, Hing Sham, Regina M Reilly, Michael E Brune, Philip R Kym
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  ABSTRACT: A highly potent and selective DGAT-1 inhibitor was identified and used in rodent models of obesity and postprandial chylomicron excursion to validate DGAT-1 inhibition as a novel approach for the treatment of metabolic diseases. Specifically, compound 4a conferred weight loss and a reduction in liver triglycerides when dosed chronically in DIO mice and depleted serum triglycerides following a lipid challenge in a dose-dependent manner, thus, reproducing major phenotypical characteristics of DGAT-1(-/-) mice.
  Journal of Medicinal Chemistry 03/2008; 51(3):380-3. · 5.25 Impact Factor
• Article: Activity of a potent hepatitis C virus polymerase inhibitor in the chimpanzee model.

  Chih-Ming Chen, Yupeng He, Liangjun Lu, Hock Ben Lim, Rakesh L Tripathi, Tim Middleton, Lisa E Hernandez, David W A Beno, Michelle A Long, Warren M Kati, Todd D Bosse, Daniel P Larson, Rolf Wagner, Robert E Lanford, William E Kohlbrenner, Dale J Kempf, Tami J Pilot-Matias, Akhteruzzaman Molla
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  ABSTRACT: A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 h, and its bioavailability was >60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log(10) copies RNA/ml for genotype 1a- and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.
  Antimicrobial Agents and Chemotherapy 01/2008; 51(12):4290-6. · 4.84 Impact Factor
• Article: Discovery of potent, selective, orally bioavailable stearoyl-CoA desaturase 1 inhibitors.

  Gang Liu, John K Lynch, Jennifer Freeman, Bo Liu, Zhili Xin, Hongyu Zhao, Michael D Serby, Philip R Kym, Tom S Suhar, Harriet T Smith, Ning Cao, Ruojing Yang, Rich S Janis, Joel A Krauser, Steven P Cepa, David W A Beno, Hing L Sham, Christine A Collins, Teresa K Surowy, Heidi S Camp
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  ABSTRACT: Stearoyl-CoA desaturase 1 (SCD1) catalyzes the committed step in the biosynthesis of monounsaturated fatty acids from saturated, long-chain fatty acids. Studies with SCD1 knockout mice have established that these animals are lean and protected from leptin deficiency-induced and diet-induced obesity, with greater whole body insulin sensitivity than wild-type animals. In this work, we have discovered a series of potent, selective, orally bioavailable SCD1 inhibitors based on a known pyridazine carboxamide template. The representative lead inhibitor 28c also demonstrates excellent cellular activity in blocking the conversion of saturated long-chain fatty acid-CoAs (LCFA-CoAs) to monounsaturated LCFA-CoAs in HepG2 cells.
  Journal of Medicinal Chemistry 07/2007; 50(13):3086-100. · 5.25 Impact Factor
• Article: Discovery and structure-activity relationships of piperidinone- and piperidine-constrained phenethylamines as novel, potent, and selective dipeptidyl peptidase IV inhibitors.

  Zhonghua Pei, Xiaofeng Li, Thomas W von Geldern, Kenton Longenecker, Daisy Pireh, Kent D Stewart, Bradley J Backes, Chunqiu Lai, Thomas H Lubben, Stephen J Ballaron, David W A Beno, Anita J Kempf-Grote, Hing L Sham, James M Trevillyan
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  ABSTRACT: Dipeptidyl peptidase IV (DPP4) inhibitors are emerging as a new class of therapeutic agents for the treatment of type 2 diabetes. They exert their beneficial effects by increasing the levels of active glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are two important incretins for glucose homeostasis. Starting from a high-throughput screening hit, we were able to identify a series of piperidinone- and piperidine-constrained phenethylamines as novel DPP4 inhibitors. Optimized compounds are potent, selective, and have good pharmacokinetic profiles.
  Journal of Medicinal Chemistry 05/2007; 50(8):1983-7. · 5.25 Impact Factor
• Article: N-{3-[2-(4-alkoxyphenoxy)thiazol-5-yl]-1-methylprop-2-ynyl}carboxy derivatives as acetyl-coA carboxylase inhibitors--improvement of cardiovascular and neurological liabilities via structural modifications.

  Yu Gui Gu, Moshe Weitzberg, Richard F Clark, Xiangdong Xu, Qun Li, Nathan L Lubbers, Yi Yang, David W A Beno, Deborah L Widomski, Tianyuan Zhang, [......], Robert F Keyes, Jeffrey F Waring, Sherry L Carroll, Xiaojun Wang, Rongqi Wang, Christine H Healan-Greenberg, Eric A Blomme, Bruce A Beutel, Hing L Sham, Heidi S Camp
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  ABSTRACT: A preliminary safety evaluation of ACC2 inhibitor 1-(S) revealed serious neurological and cardiovascular liabilities of this chemotype. A systematic structure-toxicity relationship study identified the alkyne linker as the key motif responsible for these adverse effects. Toxicogenomic studies in rats showed that 1-(R) and 1-(S) induced gene expression patterns similar to that seen with several known cardiotoxic agents such as doxorubicin. Replacement of the alkyne with alternative linker groups led to a new series of ACC inhibitors with drastically improved cardiovascular and neurological profiles.
  Journal of Medicinal Chemistry 04/2007; 50(5):1078-82. · 5.25 Impact Factor
• Article: Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit.

  Bradley J Backes, Kenton Longenecker, Gregory L Hamilton, Kent Stewart, Chunqiu Lai, Hana Kopecka, Thomas W von Geldern, David J Madar, Zhonghua Pei, Thomas H Lubben, Bradley A Zinker, Zhenping Tian, Stephen J Ballaron, Michael A Stashko, Amanda K Mika, David W A Beno, Anita J Kempf-Grote, Candace Black-Schaefer, Hing L Sham, James M Trevillyan
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  ABSTRACT: A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal.
  Bioorganic & Medicinal Chemistry Letters 04/2007; 17(7):2005-12. · 2.55 Impact Factor
• Article: Discovery of adamantane ethers as inhibitors of 11beta-HSD-1: Synthesis and biological evaluation.

  Jyoti R Patel, Qi Shuai, Jurgen Dinges, Marty Winn, Marina Pliushchev, Steven Fung, Katina Monzon, William Chiou, Jiahong Wang, Liping Pan, [......], Russell Judge, Wenying Qin, Hovis M Imade, Deanne Stolarik, David W A Beno, Michael Brune, Linda E Chovan, Hing L Sham, Peer Jacobson, J T Link
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  ABSTRACT: A novel class of adamantane ethers 11beta-hydroxysteroid hydrogenase type I inhibitors has been discovered. These compounds have excellent HSD-1 potency and selectivity against HSD-2. The structure-activity relationships, selectivity, metabolism, PK, ex vivo pharmacodynamic data, and an X-ray crystal structure of one of these inhibitors bound to h-HSD-1 are discussed.
  Bioorganic & Medicinal Chemistry Letters 03/2007; 17(3):750-5. · 2.55 Impact Factor
• Article: Constrained 7-fluorocarboxychromone-4-aminopiperidine based Melanin-concentrating hormone receptor 1 antagonists: the effects of chirality on substituted indan-1-ylamines.

  Andrew J Souers, Rajesh R Iyengar, Andrew S Judd, David W A Beno, Ju Gao, Gang Zhao, Michael E Brune, James J Napier, Mathew M Mulhern, John K Lynch, [......], Eugene N Bush, Robin Shapiro, Brian A Droz, Victoria Knourek-Segel, Lisa E Hernandez, Kennan C Marsh, Regina M Reilly, Hing L Sham, Christine A Collins, Philip R Kym
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  ABSTRACT: The incorporation of constrained tertiary amines into an existing class of N-benzyl-4-aminopiperidinyl chromone-based MCHr1 antagonists led to the identification of a series of chiral racemic compounds that displayed good to excellent functional potency, binding affinity, and selectivity over the hERG channel. Further separation of two distinct chiral racemic compounds into their corresponding pairs of enantiomers revealed a considerable selectivity for MCHr1 for one configuration, in addition to a striking difference in oral exposure between one pair of enantiomers in diet-induced obese mice. Oral administration of the most potent compound in this class in the same animal model led to significant reduction of fat mass in a semi-chronic model for weight loss.
  Bioorganic & Medicinal Chemistry Letters 03/2007; 17(4):884-9. · 2.55 Impact Factor
• Article: Discovery and metabolic stabilization of potent and selective 2-amino-N-(adamant-2-yl) acetamide 11beta-hydroxysteroid dehydrogenase type 1 inhibitors.

  Jeffrey J Rohde, Marina A Pliushchev, Bryan K Sorensen, Dariusz Wodka, Qi Shuai, Jiahong Wang, Steven Fung, Katina M Monzon, William J Chiou, Liping Pan, [......], Kennan C Marsh, David W A Beno, Thomas A Fey, Brian A Droz, Michael E Brune, Heidi S Camp, Hing L Sham, Ernst Uli Frevert, Peer B Jacobson, J T Link
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  ABSTRACT: Starting from a rapidly metabolized adamantane 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor 22a, a series of E-5-hydroxy-2-adamantamine inhibitors, exemplified by 22d and (+/-)-22f, was discovered. Many of these compounds are potent inhibitors of 11beta-HSD1 and are selective over 11beta-HSD2 for multiple species (human, mouse, and rat), unlike other reported species-selective series. These compounds have good cellular potency and improved microsomal stability. Pharmacokinetic profiling in rodents indicated moderate to large volumes of distribution, short half-lives, and a pharmacokinetic species difference with the greatest exposure measured in rat with 22d. One hour postdose liver, adipose, and brain tissue 11beta-HSD1 inhibition was confirmed with (+/-)-22f in a murine ex vivo assay. Although 5,7-disubstitued-2-adamantamines provided greater stability, a single, E-5-position, polar functional group afforded inhibitors with the best combination of stability, potency, and selectivity. These results indicate that adamantane metabolic stabilization sufficient to obtain short-acting, potent, and selective 11beta-HSD1 inhibitors has been discovered.
  Journal of Medicinal Chemistry 02/2007; 50(1):149-64. · 5.25 Impact Factor
• Article: Hemodynamic effects of potent and selective JNK inhibitors in anesthetized rats: implication for targeting protein kinases in metabolic diseases.

  Gang Liu, Hongyu Zhao, Bo Liu, Zhili Xin, Mei Liu, Michael D Serby, Nathan L Lubbers, Deborah L Widomski, James S Polakowski, David W A Beno, James M Trevillyan, Hing L Sham
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  ABSTRACT: The hemodynamic effects of a series of potent and selective 4-aminopyridine carboxamide-based pan-JNK inhibitors were assessed in an anesthetized rat model. The effects of these agents on mean arterial pressure, heart rate, cardiac contractility, and peripheral vascular resistance are described, and the implication for targeting protein kinases in metabolic diseases is discussed.
  Bioorganic & Medicinal Chemistry Letters 02/2007; 17(2):495-500. · 2.55 Impact Factor
• Article: Discovery of ((4R,5S)-5-amino-4-(2,4,5- trifluorophenyl)cyclohex-1-enyl)-(3- (trifluoromethyl)-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (ABT-341), a highly potent, selective, orally efficacious, and safe dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

  Zhonghua Pei, Xiaofeng Li, Thomas W von Geldern, David J Madar, Kenton Longenecker, Hong Yong, Thomas H Lubben, Kent D Stewart, Bradley A Zinker, Bradley J Backes, [......], Stephen J Ballaron, Michael A Stashko, Amanda K Mika, David W A Beno, Glenn A Reinhart, Ryan M Fryer, Lee C Preusser, Anita J Kempf-Grote, Hing L Sham, James M Trevillyan
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  ABSTRACT: Dipeptidyl peptidase IV (DPP4) deactivates glucose-regulating hormones such as GLP-1 and GIP, thus, DPP4 inhibition has become a useful therapy for type 2 diabetes. Optimization of the high-throughput screening lead 6 led to the discovery of 25 (ABT-341), a highly potent, selective, and orally bioavailable DPP4 inhibitor. When dosed orally, 25 dose-dependently reduced glucose excursion in ZDF rats. Amide 25 is safe in a battery of in vitro and in vivo tests and may represent a new therapeutic agent for the treatment of type 2 diabetes.
  Journal of Medicinal Chemistry 12/2006; 49(22):6439-42. · 5.25 Impact Factor
• Article: Discovery of 2-[4-{{2-(2S,5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]- 4-methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279): a very potent, selective, effective, and well-tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes.

  David J Madar, Hana Kopecka, Daisy Pireh, Hong Yong, Zhonghua Pei, Xiaofeng Li, Paul E Wiedeman, Stevan W Djuric, Thomas W Von Geldern, Michael G Fickes, [......], Bradley A Zinker, Amanda K Mika, David W A Beno, Anita J Kempf-Grote, James Polakowski, Jason Segreti, Glenn A Reinhart, Ryan M Fryer, Hing L Sham, James M Trevillyan
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  ABSTRACT: Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.
  Journal of Medicinal Chemistry 11/2006; 49(21):6416-20. · 5.25 Impact Factor
• Article: Discovery and pharmacological evaluation of growth hormone secretagogue receptor antagonists.

  Zhili Xin, Michael D Serby, Hongyu Zhao, Christi Kosogof, Bruce G Szczepankiewicz, Mei Liu, Bo Liu, Charles W Hutchins, Kathy A Sarris, Ethan D Hoff, [......], Eugene N Bush, Brian A Droz, Thomas A Fey, Victoria E Knourek-Segel, Robin Shapiro, Peer B Jacobson, David W A Beno, Teresa M Turner, Hing L Sham, Gang Liu
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  ABSTRACT: The discovery and pharmacological evaluation of potent, selective, and orally bioavailable growth hormone secretagogue receptor (GHS-R) antagonists are reported. Previously, 2,4-diaminopyrimidine-based GHS-R antagonists reported from our laboratories have been shown to be dihydrofolate reductase (DHFR) inhibitors. By comparing the X-ray crystal structure of DHFR docked with our GHS-R antagonists and GHS-R modeling, we designed and synthesized a series of potent and DHFR selective GHS-R antagonists with good pharmacokinetic (PK) profiles. An amide derivative 13d (Ca2+ flux IC50 = 188 nM, [brain]/[plasma] = 0.97 @ 8 h in rat) showed a 10% decrease in 24 h food intake in rats, and over 5% body weight reduction after 14-day oral treatment in diet-induced obese (DIO) mice. In comparison, a urea derivative 14c (Ca2+ flux IC50 = 7 nM, [brain]/[plasma] = 0.0 in DIO) failed to show significant effect on food intake in the acute feeding DIO model. These observations demonstrated for the first time that peripheral GHS-R blockage with small molecule GHS-R antagonists might not be sufficient for suppressing appetite and inducing body weight reduction.
  Journal of Medicinal Chemistry 08/2006; 49(15):4459-69. · 5.25 Impact Factor
• Article: Discovery, structure-activity relationship, and pharmacological evaluation of (5-substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as potent dipeptidyl peptidase IV inhibitors.

  Zhonghua Pei, Xiaofeng Li, Kenton Longenecker, Thomas W von Geldern, Paul E Wiedeman, Thomas H Lubben, Bradley A Zinker, Kent Stewart, Stephen J Ballaron, Michael A Stashko, [......], Todd S McDermott, Lakshmi Bhagavatula, Michael G Fickes, Daisy Pireh, Larry R Solomon, Marc R Lake, Rohinton Edalji, Elizabeth H Fry, Hing L Sham, James M Trevillyan
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  ABSTRACT: A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors. Optimized analogues are extremely potent with subnanomolar K(i)'s, are chemically stable, show very little potency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against related peptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in an oral glucose tolerance test in ZDF rats.
  Journal of Medicinal Chemistry 07/2006; 49(12):3520-35. · 5.25 Impact Factor
• Article: 2,4-diaminopyrimidine derivatives as potent growth hormone secretagogue receptor antagonists.

  Michael D Serby, Hongyu Zhao, Bruce G Szczepankiewicz, Christi Kosogof, Zhili Xin, Bo Liu, Mei Liu, Lissa T J Nelson, Wiweka Kaszubska, H Douglas Falls, [......], Brian A Droz, Victoria E Knourek-Segel, Thomas A Fey, Michael E Brune, David W A Beno, Theresa M Turner, Christine A Collins, Peer B Jacobson, Hing L Sham, Gang Liu
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  ABSTRACT: Ghrelin, a gut-derived orexigenic hormone, is an endogenous ligand of the growth hormone secretagogue receptor (GHS-R). Centrally administered ghrelin has been shown to cause hunger and increase food intake in rodents. Inhibition of ghrelin actions with ghrelin antibody, peptidyl GHS-R antagonists, and antisense oligonucleosides resulted in weight loss and food intake decrease in rodents. Here we report the effects of GHS-R antagonists, some of which were potent, selective, and orally bioavailable. A structure-activity relationship study led to the discovery of 8a, which was effective in decreasing food intake and body weight in several acute rat studies.
  Journal of Medicinal Chemistry 05/2006; 49(8):2568-78. · 5.25 Impact Factor