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J Robert Merritt,
Ray James,
Vidyadhar M Paradkar, Chongwu Zhang,
Ruiyan Liu,
Jinqi Liu,
Biji Jacob,
Camelia Chiriac,
Michael J Ohlmeyer,
Elizabeth Quadros,
Pamela Wines,
Jennifer Postelnek,
Catherine M Hicks,
Weiqing Chen,
Earl F Kimble,
Linda O'Brien,
Nicole White,
Hema Desai,
Kenneth C Appell,
Maria L Webb
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ABSTRACT: A novel series of pyrrolidine heterocycles was prepared and found to show potent inhibitory activity of CCR1 binding and CCL3 mediated chemotaxis of a CCR1-expressing cell line. A potent, optimized triazole lead from this series was found to have acceptable pharmacokinetics and microsomal stability in rat and is suitable for further optimization and development.
Bioorganic & medicinal chemistry letters 09/2010; 20(18):5477-9. · 2.65 Impact Factor
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Bin Shao,
Sam Victory,
Victor I Ilyin,
R Richard Goehring,
Qun Sun,
Derk Hogenkamp,
Diane D Hodges,
Khondaker Islam,
Deyou Sha, Chongwu Zhang,
Phong Nguyen,
Silvia Robledo,
George Sakellaropoulos,
Richard B Carter
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ABSTRACT: In the search for more efficacious drugs to treat neuropathic pain states, a series of phenoxyphenyl pyridines was designed based on 4-(4-flurophenoxy)benzaldehyde semicarbazone. Through variation of the substituents on the pyridine ring, several potent state-dependent sodium channel inhibitors were identified. From these compounds, 23 dose dependently reversed tactile allodynia in the Chung model of neuropathic pain. Administered orally at 10 mg/kg the level of reversal was ca. 50%, comparable to the effect of carbamazepine administered orally at 100 mg/kg.
Journal of Medicinal Chemistry 09/2004; 47(17):4277-85. · 5.25 Impact Factor
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ABSTRACT: Organophosphorus esters 9, 10, 14, and 15 prepared via reaction of diethyl- and diphenylphosphoryl chloride, di(o-tolyl)phosphinyl chloride, and 2,8-dimethylphenoxaphosphinyl chloride with HOAt are excellent coupling reagents for peptide synthesis which are generally superior to their uronium/guanidinium analogues and HOBt- or HODhbt-derived phosphate ester counterparts in minimizing loss of configuration during segment coupling. The phosphinyl analogues are more shelf-stable than the phosphoryl systems. The new reagents have been tested in segment couplings leading to two tripeptides (20, 21) and a hexapeptide 22. Outstanding utility is also shown for the solid-phase assembly of the ACP decapeptide. Similar results were obtained with the 2- and 4-nitro- and 2,4-dinitrophenylsulfonyl esters derived from HOAt.
The Journal of Organic Chemistry 02/2004; 69(1):62-71. · 4.45 Impact Factor
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Qun Sun,
Laykea Tafesse,
Khondaker Islam,
Xiaoming Zhou,
Sam F Victory, Chongwu Zhang,
Mohamed Hachicha,
Lori A Schmid,
Aniket Patel,
Yakov Rotshteyn,
Kenneth J Valenzano,
Donald J Kyle
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ABSTRACT: A series of 4-(2-pyridyl)piperazine-1-carboxamide analogues based on the lead compound 1 was synthesized and evaluated for VR1 antagonist activity in capsaicin-induced (CAP) and pH (5.5)-induced (pH) FLIPR assays in a rat VR1-expressing HEK293 cell line. Potent VR1 antagonists were identified through SAR studies. From these studies, 18 was found to be very potent in the in vitro assay [IC(50)=4.8 nM (pH) and 35 nM (CAP)] and orally available in rat (F%=15.1).
Bioorganic & Medicinal Chemistry Letters 11/2003; 13(20):3611-6. · 2.55 Impact Factor
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ABSTRACT: To address the targeting of G protein-coupled receptors to caveolae-related lipid rafts (CLR), we studied the human B2 (B2R) and B1 (B1R) bradykinin receptor subtypes in HEK293 cells. CLR were enriched on the basis of their unique buoyant density and composition of cholesterol, caveolin-1, and flotillin-1 but not clathrin. CLR contained B2R and B1R as determined by both receptor immunoblotting and the increase in specific activity of receptor agonist binding to cells at both 4 and 37 degrees C when binding was followed by CLR enrichment. B2R was highly enriched in this fraction, whereas B1R was not enriched. Furthermore, acid washing of cells prior to cell disruption minimally affected the CLR-associated B2R agonist binding, whereas it dissociated a major portion of the CLR-associated B1R agonist binding. In addition, when agonist binding at 4 degrees C was followed by an increase in the temperature to 37 degrees C, B2R agonist binding in CLR transiently increased, and this increase was dependent on the C-terminal domain. On the other hand, B1R agonist binding remained unchanged and was independent of the C-terminal domain. Our results show that B2R is constitutively targeted to CLR in HEK293 cells and appears to shuttle the agonist through these domains, whereas B1R may be there by default.
Biochemistry 01/2003; 41(48):14340-7. · 3.42 Impact Factor
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ABSTRACT: The ORL-1 receptor has recently been cloned and is implicated in a wide variety of physiological and pathophysiological processes. Toward the goal of elucidating important features of the receptor-bound conformation of the endogenous ligand, nociceptin (NC), several conformationally constrained analogues were prepared. Either alpha-aminoisobutyric acid (Aib) or N-methylalanine (MeAla) were inserted as replacement(s) for Ala7, Ala11, or Ala15 in the native NC sequence (FGGFTGARKSARKLANQ). In vitro assays measuring human ORL-1 receptor affinity (competition binding against [3H] NC), functional potency ([35S]GTP gamma S), and efficacy (as compared to NC) were performed for each new peptide. The receptor affinities of the Aib-containing peptides generally matched NC, showing K(i)'s in the range of 0.1-0.5 nM. By comparison, the receptor affinities of the MeAla-containing peptides were significantly diminished. Peptide 14 (FGGFTG[Aib]RKS[Aib]RKLANQ-NH2), which contains two constrained alanine residues (positions 7 and 11) and a C-terminal amide modification, was found to be a very potent agonist with K(i) = 0.05 nM and EC50 = 0.08 nM in the human ORL-1 assays. The data support a hypothesis that the receptor-bound form of NC might adopt an amphipathic helix in the "address" segment of the sequence.
Journal of Medicinal Chemistry 12/2002; 45(24):5280-6. · 5.25 Impact Factor
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Louis A Carpino,
Hideko Imazumi,
Ayman El-Faham,
Fernando J Ferrer, Chongwu Zhang,
Yunsub Lee,
Bruce M Foxman,
Peter Henklein,
Christiane Hanay,
Clemens Mügge,
Holger Wenschuh,
Jana Klose,
Michael Beyermann,
Michael Bienert
Angewandte Chemie International Edition 03/2002; 41(3):441-5. · 13.45 Impact Factor
