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Charles J McIntyre,
John A McCauley,
Bohumil Bednar,
Rodney A Bednar,
John W Butcher,
David A Claremon,
Michael E Cunningham, Roger M Freidinger,
Stanley L Gaul,
Carl F Homnick,
Ken S Koblan,
Scott D Mosser,
Joseph J Romano,
Nigel J Liverton
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ABSTRACT: A novel series of annulated tricyclic compounds was synthesized and evaluated as NMDA/NR2B antagonists. Structure-activity development was directed towards in vitro optimization of NR2B activity and selectivity over the hERG K(+) channel. Preferred compounds were subsequently evaluated for selectivity in an alpha(1)-adrenergic receptor binding counter-screen and a cell-based assay of NR2B activity.
Bioorganic & medicinal chemistry letters 08/2009; 19(17):5132-5. · 2.65 Impact Factor
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ABSTRACT: The previously unknown 3-aminomethyl-1,3-dihydro-5-(2′-fluorophenyl)-2H,4-benzodiazepin-2-one, 3a, was synthesized in two steps as a racemate. In the chiral series, 3(S)-azidocarbonylmethyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one, 12b, was prepared from Nα-Cbz-β-methylaspartate in five synthetic operations and subjected to Curtius rearrangement. The intermediate isocyanate was trapped intramolecularly by the 5-imine nitrogen of the benzodiazepine ring in 12b. This unanticipated result runs counter to the generally held dictum that the isocyanate group has a strictly linear shape.
Journal of Heterocyclic Chemistry 03/2009; 27(3):631 - 636. · 1.22 Impact Factor
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Dai-Shi Su,
John L Lim,
Elizabeth Tinney,
Bang-Lin Wan,
Kathy L Murphy,
Duane R Reiss,
C Meacham Harrell,
Stacy S O'Malley,
Rick W Ransom,
Raymond S L Chang,
Douglas J Pettibone,
Jian Yu,
Cuyue Tang,
Thomayant Prueksaritanont, Roger M Freidinger,
Mark G Bock,
Neville J Anthony
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ABSTRACT: Selective bradykinin (BK) B 1 receptor antagonists could be novel therapeutic agents for the treatment of pain and inflammation. Elucidation of the structure activity relationships of the structurally novel HTS lead compound 1 provided potent hBK B 1 receptor antagonists with excellent receptor occupancy in the CNS of hBK B 1 transgenic rats.
Journal of Medicinal Chemistry 08/2008; 51(13):3946-52. · 4.80 Impact Factor
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Michael R Wood,
Kathy M Schirripa,
June J Kim,
Scott D Kuduk,
Ronald K Chang,
Christina N Di Marco,
Robert M DiPardo,
Bang-Lin Wan,
Kathy L Murphy,
Richard W Ransom, [......],
Qin Mei,
Jian Yu,
Dennis L Bohn,
Frank C Clayton,
Emily D Adarayn,
Gary R Sitko,
Yvonne M Leonard, Roger M Freidinger,
Douglas J Pettibone,
Mark G Bock
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ABSTRACT: Antagonism of the bradykinin B(1) receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists incorporating alpha-hydroxy amides were designed that display low-nanomolar affinity for the human bradykinin B(1) receptor and good bioavailability in the rat and dog. In addition, these functionally active compounds show high passive permeability and low susceptibility to phosphoglycoprotein mediated efflux, predictive of good CNS exposure.
Bioorganic & medicinal chemistry letters 02/2008; 18(2):716-20. · 2.65 Impact Factor
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Dai-Shi Su,
John L Lim,
M Kristine Markowitz,
Bang-Lin Wan,
Kathy L Murphy,
Duane R Reiss,
C Meacham Harrell,
Stacy S O'Malley,
Rick W Ransom,
Raymond S L Chang,
Douglas J Pettibone,
Cuyue Tang,
Thomayant Prueksaritanont, Roger M Freidinger,
Mark G Bock
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ABSTRACT: Selective bradykinin (BK) B(1) receptor antagonists have been shown to be antinociceptive in animal models and could be novel therapeutic agents for the treatment of pain and inflammation. Elucidation of the structure-activity relationships of the biphenyl moiety of the lead compound 1 provided a potent new structural class of BK B(1) receptor antagonists.
Bioorganic & Medicinal Chemistry Letters 07/2007; 17(11):3006-9. · 2.55 Impact Factor
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Michael R Wood,
Kathy M Schirripa,
June J Kim,
Bang-Lin Wan,
Kathy L Murphy,
Richard W Ransom,
Raymond S L Chang,
Cuyue Tang,
Thomayant Prueksaritanont,
Theodore J Detwiler,
Lisa A Hettrick,
Elizabeth R Landis,
Yvonne M Leonard,
Julie A Krueger,
Sidney D Lewis,
Douglas J Pettibone, Roger M Freidinger,
Mark G Bock
[show abstract]
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ABSTRACT: Antagonism of the bradykinin B1 receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists were designed that display low-nanomolar affinity for the human bradykinin B1 receptor and good bioavailability in the rat.
Journal of Medicinal Chemistry 03/2006; 49(4):1231-4. · 5.25 Impact Factor
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ABSTRACT: SAR study of the biphenyl region of 2,3-diaminopyridine bradykinin B1 antagonists was investigated with non-aromatic carbo- and heterocyclic rings. A piperidine ring was found to be a good replacement for the proximal phenyl ring while replacement of the distal phenyl was optimal with a cyclohexyl group leading to a dramatic improvement in affinity for the B1 receptor.
Bioorganic & Medicinal Chemistry Letters 10/2005; 15(17):3925-9. · 2.55 Impact Factor
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Dong-Mei Feng,
Jenny M Wai,
Scott D Kuduk,
Christina Ng,
Kathy L Murphy,
Richard W Ransom,
Duane Reiss,
Raymond S L Chang,
Charles M Harrell,
Tanya MacNeil,
Cuyue Tang,
Thomayant Prueksaritanont, Roger M Freidinger,
Douglas J Pettibone,
Mark G Bock
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ABSTRACT: A novel class of 2,3-diaminopyridine bradykinin B1 receptor antagonists is disclosed. Structure-activity relationship studies (SARs) that led to compounds with significantly improved potency and pharmacokinetic properties relative to the lead compound are described.
Bioorganic & Medicinal Chemistry Letters 06/2005; 15(9):2385-8. · 2.55 Impact Factor
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Sookhee N Ha,
Pat J Hey,
Rick W Ransom,
C Meacham Harrell,
Kathryn L Murphy,
Ray Chang,
Tsing-Bau Chen,
Dai-Shi Su,
M Kristine Markowitz,
Mark G Bock, Roger M Freidinger,
Fred J Hess
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ABSTRACT: We report the first homology model of human bradykinin receptor B1 generated from the crystal structure of bovine rhodopsin as a template. Using an automated docking procedure, two B1 receptor antagonists of the dihydroquinoxalinone structural class were docked into the receptor model. Site-directed mutagenesis data of the amino acid residues in TM1, TM3, TM6, and TM7 were incorporated to place the compounds in the binding site of the homology model of the human B1 bradykinin receptor. The best pose in agreement with the mutation data was selected for detailed study of the receptor-antagonist interaction. To test the model, the calculated antagonist-receptor binding energy was correlated with the experimentally measured binding affinity (K(i)) for nine dihydroquinoxalinone analogs. The model was used to gain insight into the molecular mechanism for receptor function and to optimize the dihydroquinoxalinone analogs.
Biochemical and Biophysical Research Communications 06/2005; 331(1):159-66. · 2.48 Impact Factor
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Dai-Shi Su,
M Kristine Markowitz,
Kathy L Murphy,
Bang-Lin Wan,
Matthew M Zrada,
C Meacham Harrell,
Stacy S O'Malley,
J Fred Hess,
Rick W Ransom,
Ray S Chang,
Michael A Wallace,
Conrad E Raab,
Dennis C Dean,
Douglas J Pettibone, Roger M Freidinger,
Mark G Bock
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ABSTRACT: We have developed an efficient and selective radioligand, the [35S]-radiolabeled dihydroquinoxalinone derivative, 4, for an ex vivo receptor occupancy assay in transgenic rats over-expressing the human bradykinin B1 receptor.
Bioorganic & Medicinal Chemistry Letters 01/2005; 14(24):6045-8. · 2.55 Impact Factor
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Scott D Kuduk,
Christina Ng,
Dong-Mei Feng,
Jenny M-C Wai,
Raymond S L Chang,
Charles M Harrell,
Kathy L Murphy,
Richard W Ransom,
Duane Reiss,
Magnus Ivarsson,
Glenn Mason,
Susan Boyce,
Cuyue Tang,
Thomayant Prueksaritanont, Roger M Freidinger,
Douglas J Pettibone,
Mark G Bock
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ABSTRACT: Bradykinin B1 receptor antagonists embody a potentially novel approach for the treatment of chronic pain and inflammation. A series of 2,3-diaminopyridine B1 antagonists was optimized to have sub-nanomolar affinity and good pharmacokinetic properties. Lead compounds were shown to exhibit good efficacy in rabbit in vivo models of pain and inflammation.
Journal of Medicinal Chemistry 01/2005; 47(26):6439-42. · 5.25 Impact Factor
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Richard W Ransom,
Charles M Harrell,
Duane R Reiss,
Kathryn L Murphy,
Raymond S L Chang,
J Fred Hess,
Patricia J Miller,
Stacey S O'Malley,
Pat J Hey,
Priya Kunapuli,
Dai-Shi Su,
M Kristine Markowitz,
Michael A Wallace,
Conrad E Raab,
Allen N Jones,
Dennis C Dean,
Douglas J Pettibone, Roger M Freidinger,
Mark G Bock
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ABSTRACT: Compound A (N-[2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]ethyl]-2-[(2R)-1-(2-napthylsulfonyl)-3-oxo-1,2,3,4-tetrahydroquinoxalin-2-yl]acetamide) is a member of a new class of aryl sulfonamide dihydroquinoxalinone bradykinin B1 receptor antagonists that should be useful pharmacological tools. Here we report on some of the pharmacological properties of compound A as well as the characterization of [35S]compound A as the first nonpeptide bradykinin B1 receptor radioligand. Compound A inhibited tritiated peptide ligand binding to the cloned human, rabbit, dog, and rat bradykinin B1 receptors expressed in CHO cells with Ki values of 0.016, 0.050, 0.56, and 29 nM, respectively. It was inactive at 10 microM in binding assays with the cloned human bradykinin B2 receptor. In functional antagonist assays with the cloned bradykinin B1 receptors, compound A inhibited agonist-induced signaling with activities consistent with the competition binding results, but had no antagonist activity at the bradykinin B2 receptor. Compound A was also found to be a potent antagonist in a rabbit aorta tissue bath preparation and to effectively block des-Arg9 bradykinin depressor responses in lipopolysaccharide-treated rabbit following intravenous administration. The binding of [35S]compound A was evaluated with the cloned bradykinin B1 receptors. In assays with human, rabbit, and dog receptors, [35S]compound A labeled a single site with Kd values of 0.012, 0.064, and 0.37 nM, respectively, and with binding site densities equivalent to those obtained using the conventional tritiated peptide ligands. Binding assays with the cloned rat bradykinin B1 receptor were not successful, presumably due to the low affinity of the ligand for this species receptor. There was no specific binding of the ligand detected in CHO cells expressing the human bradykinin B2 receptor. In assays with the cloned human bradykinin B1 receptor, the pharmacologies of the binding of [35S]compound A and [3H][Leu9]des-Arg10-kallidin were the same. The high signal-to-noise ratio obtained with [35S]compound A will allow this ligand to be a very useful tool for future investigations of the bradykinin B1 receptor.
European Journal of Pharmacology 10/2004; 499(1-2):77-84. · 2.52 Impact Factor
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Georgia B McGaughey,
Gaetano Barbato,
Elisabetta Bianchi, Roger M Freidinger,
Victor M Garsky,
William M Hurni,
Joseph G Joyce,
Xiaoping Liang,
Michael D Miller,
Antonello Pessi,
John W Shiver,
Michael J Bogusky
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ABSTRACT: The HIV-1 gp41 envelope glycoprotein mediates fusion of the viral and cellular membranes. The core of the gp41 ectodomain undergoes a receptor-triggered conformational transition forming a trimeric, alpha-helical coiled-coil structure. This trimer-of-hairpins species facilitates insertion of the viral envelope protein into the host cell membrane promoting viral entry. The prefusogenic conformation of gp41 is capable of stimulating a neutralizing antibody immune response and is therefore an attractive therapeutic target. Several broadly neutralizing HIV-1 monoclonal antibodies which bind to gp41 have been characterized and include 4E10, Z13 and 2F5. A conserved segment of gp41 (residues 661-684) has been identified as the epitope for the HIV-1 neutralizing antibody 2F5 (MAb 2F5). MAb 2F5 has attracted considerable attention because of the highly conserved recognition epitope and the ability to neutralize both laboratory-adapted and primary viral isolates. Antibodies which recognize the immunodominant regions of gp41 may provide protection against HIV infection if elicited at appropriate concentrations. Here we review the rational design, structure-activity relationships and conformational features of both linear and constrained peptide immunogens incorporating variants of both the 2F5 epitope and the gp41 ectodomain. This review describes a rational design approach combining structural characterization with traditional SAR to optimize MAb 2F5 antibody affinities of gp41-based peptide immunogens. The immunogens are shown to stimulate a high titer, peptide-specific immune response; however, the resulting antisera were incapable of viral neutralization. The implication of these findings with regard to structural and immunological considerations is discussed.
Current HIV Research 05/2004; 2(2):193-204. · 1.75 Impact Factor
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John A McCauley,
Cory R Theberge,
Joseph J Romano,
Susan B Billings,
Kenneth D Anderson,
David A Claremon, Roger M Freidinger,
Rodney A Bednar,
Scott D Mosser,
Stanley L Gaul, [......],
Cindra L Condra,
Menghang Xia,
Michael E Cunningham,
Bohumil Bednar,
Gary L Stump,
Joseph J Lynch,
Alison Macaulay,
Keith A Wafford,
Kenneth S Koblan,
Nigel J Liverton
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ABSTRACT: Two classes of 5-substituted benzimidazoles were identified as potent antagonists of the NR2B subtype of the N-methyl-d-aspartate (NMDA) receptor. Selected compounds show very good selectivity versus the NR2A, NR2C, and NR2D subtypes of the NMDA receptor as well as versus hERG-channel activity and alpha(1)-adrenergic binding. Benzimidazole 37a shows excellent activity in the carrageenan-induced mechanical hyperalgesia assay in rats as well as good pharmacokinetic behavior in dogs.
Journal of Medicinal Chemistry 05/2004; 47(8):2089-96. · 5.25 Impact Factor
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Roger M Freidinger
Journal of Medicinal Chemistry 01/2004; 46(26):5553-66. · 5.25 Impact Factor
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Dai-Shi Su,
M Kristine Markowitz,
Robert M DiPardo,
Kathy L Murphy,
C Meacham Harrell,
Stacy S O'Malley,
Richard W Ransom,
Raymond S L Chang,
Sookhee Ha,
Fred J Hess,
Douglas J Pettibone,
Glenn S Mason,
Susan Boyce, Roger M Freidinger,
Mark G Bock
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ABSTRACT: Bradykinin (BK) plays an important role in the pathophysiological processes accompanying pain and inflammation. Selective bradykinin B1 receptor antagonists have been shown to be anti-nociceptive in animal models and could be novel therapeutic agents for the treatment of pain and inflammation. We have explored chemical modifications in a series of dihydroquinoxalinone sulfonamides to evaluate the effects of various structural changes on biological activity. The optimization of a screening lead compound, facilitated by a homology model of the BK B1 receptor, culminated in the discovery of a potent human BK B1 receptor antagonist. Results from site-directed mutagenesis studies and experiments in an animal pain model are presented.
Journal of the American Chemical Society 07/2003; 125(25):7516-7. · 9.91 Impact Factor
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Michael R Wood,
June J Kim,
Wei Han,
Bruce D Dorsey,
Carl F Homnick,
Robert M DiPardo,
Scott D Kuduk,
Tanya MacNeil,
Kathy L Murphy,
Edward V Lis, [......],
Patricia J Miller,
Tsing-Bau Chen,
Charles M Harrell,
Raymond S L Chang,
Punam Sandhu,
Joan D Ellis,
Peter J Bondiskey,
Douglas J Pettibone, Roger M Freidinger,
Mark G Bock
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ABSTRACT: Antagonism of the bradykinin B(1) receptor was demonstrated to be a potential treatment for chronic pain and inflammation. Novel benzodiazepines were designed that display subnanomolar affinity for the bradykinin B(1) receptor (K(i) = 0.59 nM) and high selectivity against the bradykinin B(2) receptor (K(i) > 10 microM). In vivo efficacy, comparable to morphine, was demonstrated for lead compounds in a rodent hyperalgesia model.
Journal of Medicinal Chemistry 06/2003; 46(10):1803-6. · 5.25 Impact Factor
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John W Butcher,
Nigel J Liverton,
David A Claremon, Roger M Freidinger,
Nancy K Jurkiewicz,
Joseph J Lynch,
Joseph J Salata,
Jixin Wang,
Christine M Dieckhaus,
Donald E Slaughter,
Kamlesh Vyas
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ABSTRACT: Novel 5-cyclopropyl-1,4-benzodiazepin-2-ones having various N-l substituents were identified as potent and selective blockers of the slowly activating cardiac delayed rectifier potassium current (I(Ks)). Compound 11 is the most potent I(Ks) channel blocker reported to date.
Bioorganic & Medicinal Chemistry Letters 04/2003; 13(6):1165-8. · 2.55 Impact Factor
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Christopher F Claiborne,
John A McCauley,
Brian E Libby,
Neil R Curtis,
Helen J Diggle,
Janusz J Kulagowski,
Stuart R Michelson,
Kenneth D Anderson,
David A Claremon, Roger M Freidinger, [......],
Stanley L Gaul,
Thomas M Connolly,
Cindra L Condra,
Bohumil Bednar,
Gary L Stump,
Joseph J Lynch,
Alison Macaulay,
Keith A Wafford,
Kenneth S Koblan,
Nigel J Liverton
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ABSTRACT: A novel series of benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist activity. Compound 31 is orally active in a carrageenan-induced rat hyperalgesia model of pain and shows no motor coordination side effects.
Bioorganic & Medicinal Chemistry Letters 03/2003; 13(4):697-700. · 2.55 Impact Factor
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Stephen F Brady,
Joseph M Pawluczyk,
Patricia K Lumma,
Dong-Mei Feng,
Jenny M Wai,
Raymond Jones,
Deborah DeFeo-Jones,
Bradley K Wong,
Cynthia Miller-Stein,
Jiunn H Lin,
Allen Oliff, Roger M Freidinger,
Victor M Garsky
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ABSTRACT: Chemotherapy of prostate cancer with antimitotic agents such as vinblastine and doxorubicin is only marginally effective, due to dose-limiting systemic toxicity. Herein we report the development of peptidyl conjugate 5 of the cytotoxic agent vinblastine (1), along with the results of its in vitro and in vivo evaluation as a pro-drug targeted at prostate cancer cells. Prostate-derived tumors are known to produce significant amounts of prostate specific antigen (PSA), a serine protease with chymotrypsin-like properties. Earlier work in these laboratories established that an appropriately engineered peptidyl pro-drug will release active cytotoxic agent strictly within the microenvironment of the tumor tissue (Garsky, V. M., et al. J. Med.Chem. 2001, 44, 4216-4224). Conjugate 5, which features an octapeptide segment attached by an ester linkage at the 4-position of vinblastine (1), undergoes rapid cleavage by PSA (T(1/2) = 12 min) between the Gln and Ser residues. In nude mouse xenograft studies, 5 reduced circulating PSA levels by 99% and tumor weight by 85% at a dose just below its MTD. By contrast, the putative end-point metabolite, the cytotoxic agent des-acetyl vinblastine (1b), was ineffective in reducing PSA levels and tumor burden at its maximum tolerated doses. Additional data from metabolism studies on 5 support the supervention of a novel in vivo processing mechanism, the spontaneous release of 1b from a dipeptidyl intermediate driven by favorable diketopiperazine formation.
Journal of Medicinal Chemistry 11/2002; 45(21):4706-15. · 5.25 Impact Factor
