Joseph G Bruno

Publications (10)31.02 Total impact

• Article: MK-8825: a potent and selective CGRP receptor antagonist with good oral activity in rats.

  Ian M Bell, Craig A Stump, Steven N Gallicchio, Donnette D Staas, C Blair Zartman, Eric L Moore, Nova Sain, Mark Urban, Joseph G Bruno, Amy Calamari, Amanda L Kemmerer, Scott D Mosser, Christine Fandozzi, Rebecca B White, Matthew M Zrada, Harold G Selnick, Samuel L Graham, Joseph P Vacca, Stefanie A Kane, Christopher A Salvatore
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  ABSTRACT: Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo.
  Bioorganic & medicinal chemistry letters 04/2012; 22(12):3941-5. · 2.65 Impact Factor
• Article: Structure-based design and synthesis of 1,3-oxazinan-2-one inhibitors of 11β-hydroxysteroid dehydrogenase type 1.

  Zhenrong Xu, Colin M Tice, Wei Zhao, Salvacion Cacatian, Yuan-Jie Ye, Suresh B Singh, Peter Lindblom, Brian M McKeever, Paula M Krosky, Barbara A Kruk, [......], Yi Zhao, Joseph G Bruno, Jennifer Togias, Joan Guo, Rong Guo, Patrick J Carroll, Gerard M McGeehan, Linghang Zhuang, Wei He, David A Claremon
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  ABSTRACT: Structure based design led directly to 1,3-oxazinan-2-one 9a with an IC(50) of 42 nM against 11β-HSD1 in vitro. Optimization of 9a for improved in vitro enzymatic and cellular potency afforded 25f with IC(50) values of 0.8 nM for the enzyme and 2.5 nM in adipocytes. In addition, 25f has 94% oral bioavailability in rat and >1000× selectivity over 11β-HSD2. In mice, 25f was distributed to the target tissues, liver, and adipose, and in cynomolgus monkeys a 10 mg/kg oral dose reduced cortisol production by 85% following a cortisone challenge.
  Journal of Medicinal Chemistry 08/2011; 54(17):6050-62. · 4.80 Impact Factor
• Article: Novel CGRP receptor antagonists from central amide replacements causing a reversal of preferred chirality.

  Michael R Wood, Kathy M Schirripa, June J Kim, Rodney A Bednar, John F Fay, Joseph G Bruno, Eric L Moore, Scott D Mosser, Shane Roller, Christopher A Salvatore, Joseph P Vacca, Harold G Selnick
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  ABSTRACT: A previously utilized quinoline-for-N-phenylamide replacement strategy was employed against a central amide in a novel class of CGRP receptor antagonists. A unique and unexpected substitution pattern was ultimately required to maintain reasonable affinity for the CGRP receptor, while at the same time predicting acceptable heterocycle positioning for related analogs. Subsequently, specific quinoline and naphthyridine compounds were prepared which supported these structural predictions by displaying CGRP binding affinities in the 0.037-0.15 nM range.
  Bioorganic & medicinal chemistry letters 11/2010; 20(22):6827-30. · 2.65 Impact Factor
• Article: Discovery and optimization of adamantyl carbamate inhibitors of 11β-HSD1.

  Colin M Tice, Wei Zhao, Paula M Krosky, Barbara A Kruk, Jennifer Berbaum, Judith A Johnson, Yuri Bukhtiyarov, Reshma Panemangalore, Boyd B Scott, Yi Zhao, [......], Joan Guo, Rong Guo, Herbert Nar, Annette Schuler-Metz, Richard E Gregg, Katerina Leftheris, Richard K Harrison, Gerard M McGeehan, Linghang Zhuang, David A Claremon
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  ABSTRACT: Synthesis of 2-adamantyl carbamate derivatives of piperidines and pyrrolidines led to the discovery of 9a with an IC(50) of 15.2 nM against human 11β-HSD1 in adipocytes. Optimization for increased adipocyte potency, metabolic stability and selectivity afforded 11k and 11l, both of which were >25% orally bioavailable in rat.
  Bioorganic & medicinal chemistry letters 11/2010; 20(22):6725-9. · 2.65 Impact Factor
• Article: Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia.

  Christopher D Cox, Michael J Breslin, David B Whitman, John D Schreier, Georgia B McGaughey, Michael J Bogusky, Anthony J Roecker, Swati P Mercer, Rodney A Bednar, Wei Lemaire, [......], Cuyue Tang, Shane Roller, Tamara D Cabalu, Donghui Cui, George D Hartman, Steven D Young, Ken S Koblan, Christopher J Winrow, John J Renger, Paul J Coleman
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  ABSTRACT: Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.
  Journal of Medicinal Chemistry 07/2010; 53(14):5320-32. · 4.80 Impact Factor
• Article: Spirocyclic ureas: orally bioavailable 11 beta-HSD1 inhibitors identified by computer-aided drug design.

  Colin M Tice, Wei Zhao, Zhenrong Xu, Salvacion T Cacatian, Robert D Simpson, Yuan-Jie Ye, Suresh B Singh, Brian M McKeever, Peter Lindblom, Joan Guo, [......], Judith J Johnson, Yuri Bukhtiyarov, Reshma Panemangalore, Boyd B Scott, Yi Zhao, Joseph G Bruno, Linghang Zhuang, Gerard M McGeehan, Wei He, David A Claremon
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  ABSTRACT: Structure-guided drug design led to the identification of a class of spirocyclic ureas which potently inhibit human 11beta-HSD1 in vitro. Lead compound 10j was shown to be orally bioavailable in three species, distributed into adipose tissue in the mouse, and its (R) isomer 10j2 was efficacious in a primate pharmacodynamic model.
  Bioorganic & medicinal chemistry letters 02/2010; 20(3):881-6. · 2.65 Impact Factor
• Article: Novel CGRP receptor antagonists through a design strategy of target simplification with addition of molecular flexibility.

  Michael R Wood, Kathy M Schirripa, June J Kim, Amy G Quigley, Craig A Stump, Ian M Bell, Rodney A Bednar, John F Fay, Joseph G Bruno, Eric L Moore, Scott D Mosser, Shane Roller, Christopher A Salvatore, Stefanie A Kane, Joseph P Vacca, Harold G Selnick
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  ABSTRACT: A novel class of CGRP receptor antagonists was rationally designed by modifying a highly potent, but structurally complex, CGRP receptor antagonist. Initial modifications focused on simplified structures, with increased flexibility. Subsequent to the preparation of a less-potent but more flexible lead, classic medicinal chemistry methods were applied to restore high affinity (compound 22, CGRP Ki=0.035 nM) while maintaining structural diversity relative to the lead. Good selectivity against the closely related adrenomedullin-2 receptor was also achieved.
  Bioorganic & medicinal chemistry letters 09/2009; 19(19):5787-90. · 2.65 Impact Factor
• Article: Discovery of a potent, CNS-penetrant orexin receptor antagonist based on an n,n-disubstituted-1,4-diazepane scaffold that promotes sleep in rats.

  David B Whitman, Christopher D Cox, Michael J Breslin, Karen M Brashear, John D Schreier, Michael J Bogusky, Rodney A Bednar, Wei Lemaire, Joseph G Bruno, George D Hartman, [......], Richard L Kraus, Yuxing Li, Susan L Garson, Scott M Doran, Thomayant Prueksaritanont, Chunze Li, Christopher J Winrow, Kenneth S Koblan, John J Renger, Paul J Coleman
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  ABSTRACT: Silent Night: Antagonism of the orexin (or hypocretin) system has recently been identified as a novel mechanism for the treatment of insomnia. Herein, we describe discovery of a dual (OX(1)R/OX(2)R) orexin receptor antagonist featuring a 1,4-diazepane central constraint that blocks orexin signaling in vivo. In telemetry-implanted rats, oral administration of this antagonist produced a decrease in wakefulness, while increasing REM and non-REM sleep.
  ChemMedChem 06/2009; 4(7):1069-74. · 3.15 Impact Factor
• Article: The discovery of highly potent CGRP receptor antagonists.

  Craig A Stump, Ian M Bell, Rodney A Bednar, Joseph G Bruno, John F Fay, Steven N Gallicchio, Victor K Johnston, Eric L Moore, Scott D Mosser, Amy G Quigley, Christopher A Salvatore, Cory R Theberge, C Blair Zartman, Xu-Fang Zhang, Stefanie A Kane, Samuel L Graham, Joseph P Vacca, Theresa M Williams
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  ABSTRACT: Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25, CGRP K(i)=40pM). The closely related compound 27 demonstrated good oral bioavailability in dog and rhesus.
  Bioorganic & medicinal chemistry letters 11/2008; 19(1):214-7. · 2.65 Impact Factor
• Article: Cloning, characterization and site-directed mutagenesis of canine renin.

  Yuri Bukhtiyarov, Marianne Zecher, Reshma Panemangalore, Zhongren Wu, Joseph G Bruno, Jing Yuan, Zhenrong Xu, Lawrence W Dillard, Gerard M McGeehan, Richard K Harrison, Boyd B Scott
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  ABSTRACT: Inhibition of renin has been shown to be successful in managing hypertension and maintaining cardiac health. Canine models have played a key role in preclinical assessment of renin inhibitors. Here we report the cloning of canine prorenin gene. The amino acid sequence of mature canine renin was approximately 70% identical to that of human renin. The full-length prorenin was expressed in HEK 293 cells, purified and converted to its active form by trypsin-mediated cleavage of the 43 residue propeptide. The mature enzyme was characterized by steady-state kinetics using a peptide corresponding to the canine angiotensinogen sequence, Ac-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser-OH (cleavage between Leu(10)-Leu(11)). The reaction followed Michaelis-Menten kinetics with a K(M) of 120 microM and a second-order rate constant (k(cat)/K(M)) of 1.7 x 10(5) M(-)(1)s(-)(1). The enzyme was inhibited by various human renin inhibitors, but at reduced potency compared to the human renin. The basis of the species specificity was investigated by mutagenesis. Based on primary sequence and structural alignments, three mutants were prepared (G149S-S150T, V286L, G149S-S150T-V286L). Each mutant yielded catalytically active enzymes with lower specific activities than native canine renin. V286L had the greatest effect on substrate specificity, while G149S, S150T mutations produced enzymes with inhibitor profiles similar to human renin.
  Journal of Biochemistry 01/2008; 142(6):671-80. · 2.37 Impact Factor