共查询到20条相似文献,搜索用时 15 毫秒
1.
Christopher S. Burgey Craig M. Potteiger James Z. Deng Scott D. Mosser Christopher A. Salvatore Sean Yu Shane Roller Stefanie A. Kane Joseph P. Vacca Theresa M. Williams 《Bioorganic & medicinal chemistry letters》2009,19(22):6368-6372
Several novel spiropiperidine-based CGRP receptor antagonists have been developed that maintain good potency and have reduced potential for metabolism. 相似文献
2.
George Tora Andrew P. Degnan Charles M. Conway Walter A. Kostich Carl D. Davis Sokhom S. Pin Richard Schartman Cen Xu Kimberly A. Widmann John E. Macor Gene M. Dubowchik 《Bioorganic & medicinal chemistry letters》2013,23(20):5684-5688
Several new potent CGRP receptor antagonists have been prepared in which the amide bond of lead compound 1 has been replaced by bioisosteric imidazole moieties. Substitution at N-1 of the imidazole was optimized to afford compounds with comparable potency to that of lead 1. Conformational restraint of the imidazole to form tetrahydroimidazo[1,5-a]pyrazine 43 gave substantially improved permeability. 相似文献
3.
Paone DV Nguyen DN Shaw AW Burgey CS Potteiger CM Deng JZ Mosser SD Salvatore CA Yu S Roller S Kane SA Selnick HG Vacca JP Williams TM 《Bioorganic & medicinal chemistry letters》2011,21(9):2683-2686
In our ongoing efforts to develop CGRP receptor antagonists for the treatment of migraine, we aimed to improve upon telecagepant by targeting a compound with a lower projected clinical dose. Imidazoazepanes were identified as potent caprolactam replacements and SAR of the imidazole yielded the tertiary methyl ether as an optimal substituent for potency and hERG selectivity. Combination with the azabenzoxazinone spiropiperidine ultimately led to preclinical candidate 30 (MK-2918). 相似文献
4.
In guinea pig pancreatic acini rat calcitonin gene-related peptide (CGRP) increased amylase release 2-fold, salmon calcitonin had an efficacy of only 44% of that of CGRP and [Tyr0]CGRP(28-37) and human calcitonin had no actions. [Tyr0]CGRP(28-37), but not human calcitonin, antagonized the actions of CGRP in pancreatic acini with an IC50 of 3 microM. [Tyr0]CGRP(28-37) produced a parallel rightward shift in the dose-response curve for CGRP-stimulated amylase secretion. The inhibition was specific for CGRP and was reversible. Studies with 125I-CGRP demonstrated that CGRP, salmon calcitonin and [Tyr0]CGRP, but not human calcitonin, interacted with CGRP receptors on pancreatic acini. These results indicate that various CGRP-related peptides demonstrate different relationships between their abilities to occupy the CGRP receptor and to affect biologic activity, with CGRP itself being a full agonist, salmon calcitonin a partial agonist, [Tyr0]CGRP(28-37) a competitive antagonist, and human calcitonin having no actions. 相似文献
5.
Luo G Chen L Pin SS Xu C Conway CM Macor JE Dubowchik GM 《Bioorganic & medicinal chemistry letters》2012,22(8):2912-2916
Novel aspartate and succinate CGRP full antagonists were identified through core modification of a potent lead CGRP antagonist, BMS-694153. While aspartates were much less active and had a flat SAR, some of the succinates were very potent CGRP full antagonists and matched the potency of BMS-694153. The most potency resides in the S enantiomer as demonstrated through an asymmetric synthesis. 相似文献
6.
Calcitonin gene-related peptide (CGRP) receptor antagonists: investigations of a pyridinone template
Nguyen DN Paone DV Shaw AW Burgey CS Mosser SD Johnston V Salvatore CA Leonard YM Miller-Stein CM Kane SA Koblan KS Vacca JP Graham SL Williams TM 《Bioorganic & medicinal chemistry letters》2008,18(2):755-758
In our effort to find potent, orally bioavailable CGRP receptor antagonists for the treatment of migraine, a novel series based on a pyridinone template was investigated. After optimizing the privileged structure and the placement of the attached phenyl ring, systematic SAR was carried out on both the N-alkyl and C-5 aryl substituents. Several analogs with good potency and pharmacokinetic profiles were identified. 相似文献
7.
Han X Civiello RL Conway CM Cook DA Davis CD Macci R Pin SS Ren SX Schartman R Signor LJ Thalody G Widmann KA Xu C Chaturvedula PV Macor JE Dubowchik GM 《Bioorganic & medicinal chemistry letters》2012,22(14):4723-4727
We have systematically studied the effects of varying the central unnatural amino acid moiety on CGRP receptor antagonist potency and CYP inhibition in a series of ureidoamides. In this Letter, we report the discovery of compound 23, a potent CGRP receptor antagonist with only weak CYP3A4 inhibition. Unlike the triptans, compound 23 did not cause active constriction of ex vivo human cerebral arteries. At doses of 0.3-1 mg/kg (s.c.), 23 showed robust inhibition of CGRP-induced increases in marmoset facial blood flow, a validated migraine model. Ureidoamide 23 derives from a novel amino acid, 1H-indazol-5-yl substituted alanine as a tyrosine surrogate. 相似文献
8.
Xiaojun Han Rita L. Civiello Charles M. Conway Deborah A. Cook Carl D. Davis Andrew P. Degnan Xiang-Jun Jiang Robert Macci Neil R. Mathias Paul Moench Sokhom S. Pin Richard Schartman Laura J. Signor George Thalody George Tora Valerie Whiterock Cen Xu John E. Macor Gene M. Dubowchik 《Bioorganic & medicinal chemistry letters》2013,23(6):1870-1873
Various substituted indazole and benzoxazolone amino acids were investigated as d-tyrosine surrogates in highly potent CGRP receptor antagonists. Compound 3, derived from the 7-methylindazole core, afforded a 30-fold increase in CGRP binding potency compared with its unsubstituted indazole analog 1. When dosed at 0.03 mg/kg SC, compound 2 (a racemic mixture of 3 and its (S)-enantiomer) demonstrated robust inhibition of CGRP-induced increases in mamoset facial blood flow up to 105 min. The compound possesses a favorable predictive in vitro toxicology profile, and good aqueous solubility. When dosed as a nasal spray in rabbits, 3 was rapidly absorbed and showed good intranasal bioavailability (42%). 相似文献
9.
A Barakat J C Marie G Rosselin 《Comptes rendus de l'Académie des sciences. Série III, Sciences de la vie》1990,310(5):189-194
We demonstrate here that membranes prepared from beta cells which release insulin contain specific binding sites for calcitonin gene-related peptide (CGRP). The binding of 125I(His) human CGRP to beta cell membranes was protein concentration, time, temperature and pH dependent. Scatchard analysis of the data revealed a single class of binding sites with an apparent dissociation constant (Kd) of 1.5 nM and a maximal binding capacity of 19 fmol/mg of protein. Chicken CGRP inhibited the label binding whereas salmon calcitonin had only a weak effect. These results suggest that the effect of CGRP on insulin secretion is due to a direct action on beta cells. 相似文献
10.
降钙素基因相关肽(CGRP)mRNA在大鼠淋巴细胞中的表达 总被引:10,自引:0,他引:10
最近,我们研究发现大鼠胸腺和淋巴结淋巴细胞中存在降钙素基因相关肽(CGRP)样免疫反应活性。应用人工合成的可特异扩增降钙素/降钙素基因相关肽基因部分片断的寡核苷酸引物,通过逆转录-多聚酶链反应(RT-PCR),检测在大鼠脊髓背根神经节、胸腺细胞及肠系膜淋巴结淋巴细胞中是否存在CGRP mRNA,进一步研究大鼠淋巴细胞能否合成CGRP。结果显示,通过RT-PCR从脊髓背根神经节(阳性对照)、胸腺和淋 相似文献
11.
Williams TM Stump CA Nguyen DN Quigley AG Bell IM Gallicchio SN Zartman CB Wan BL Penna KD Kunapuli P Kane SA Koblan KS Mosser SD Rutledge RZ Salvatore C Fay JF Vacca JP Graham SL 《Bioorganic & medicinal chemistry letters》2006,16(10):2595-2598
High-throughput screening of the Merck sample collection identified benzodiazepinone tetralin-spirohydantoin 1 as a CGRP receptor antagonist with micromolar activity. Comparing the structure of 1 with those of earlier peptide-based antagonists such as BIBN 4096 BS, a key hydrogen bond donor-acceptor pharmacophore was hypothesized. Subsequent structure activity studies supported this hypothesis and led to benzodiazepinone piperidinyldihydroquinazolinone 7, CGRP receptor K(i)=44nM and IC(50)=38nM. Compound 7 was orally bioavailabile in rats and is a lead in the development of orally bioavailable CGRP antagonists for the treatment of migraine. 相似文献
12.
Synthesis of calcitonin gene-related peptide (CGRP) by rat arterial endothelial cells 总被引:3,自引:0,他引:3
Doi Y Kudo H Nishino T Kayashima K Kiyonaga H Nagata T Nara S Morita M Fujimoto S 《Histology and histopathology》2001,16(4):1073-1079
We investigated the protein and mRNA expression of calcitonin gene-related peptide (CGRP) in endothelial cells of the rat thoracic aorta and femoral artery. Light microscopic immunocytochemistry revealed that immunoreactivity for CGRP was preferentially located in the endothelium of both vessels. Immunoelectron microscopy showed that CGRP-immunoreactive gold particles were preferentially localized on cisterns of the rough endoplasmic reticulum and on the Weibel-Palade (WP) bodies in the endothelial cells. Prepro CGRP mRNA signals were also detected on the endothelium. Our results are the first to demonstrate that endothelial cells of both elastic and large muscular arteries synthesize CGRP and store it, in part, in WP bodies, implying that CGRP may act as an endothelium-derived relaxing factor in these vessels. 相似文献
13.
14.
Luo G Chen L Civiello R Pin SS Xu C Kostich W Kelley M Conway CM Macor JE Dubowchik GM 《Bioorganic & medicinal chemistry letters》2012,22(8):2917-2921
In our continuing efforts to identify CGRP receptor antagonists that can be dosed orally for the treatment of migraine headache, we have investigated a pyridine bioisosteric replacement of a polar amide portion of a previous lead compound, BMS-694153. Pyridine derivatives were discovered and their SAR was studied. Some of them showed excellent binding potency. However, oral bioavailability was low, even for compounds with good Caco-2 cell permeability. 相似文献
15.
Investigation of the structure/activity relationship of human calcitonin gene-related peptide (CGRP) 总被引:6,自引:0,他引:6
J R Tippins V Di Marzo M Panico H R Morris I MacIntyre 《Biochemical and biophysical research communications》1986,134(3):1306-1311
The biological activities of calcitonin gene-related peptide (CGRP) enzymic digest fragments, chemically modified products and beta-CGRP have been compared to that of intact alpha-CGRP on rat isolated paired atria. Tryptic and chymotryptic digests both produced inactive fragments. Acetylation of the N-terminal amino acid (Alanine) or either of Lys 24 or Lys 35, resulted in reduced, but measurable, biological activity. Destruction of the disulphide bridge between Cys 2 and Cys 7 abolished biological activity. Substitution of several amino acids, Asp 3, Val 22 and Asn 25, with Asn, Met and Ser respectively (beta-CGRP), produced a peptide with similar biological activity to alpha-CGRP. 相似文献
16.
Enhancement of phagocytosis by calcitonin gene-related peptide (CGRP) in cultured mouse peritoneal macrophages 总被引:1,自引:0,他引:1
Calcitonin gene-related peptide (CGRP) is widely distributed in sensory neurons and nerve fibers. To clarify the function of CGRP on the immune system, the effect of CGRP on phagocytosis by peritoneal mactophages was examined by means of flow cytofluorometry. CGRP enhanced phagocytosis of latex beads in a dose-dependent manner. Because the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) enhanced the CGRP-induced enhancement of phagocytosis, the enhancement might be mediated by cAMP. In the presence of mannan, the phagocytosis was suppressed and the CGRP-induced enhancement was also blocked, suggesting that mannose receptors on macrophages were involved in mediating the phagocytosis of latex beads, and CGRP enhanced the mannose receptor-mediated phagocytosis. The present results indicate that CGRP can modulate the function of macrophages in nerve terminals of sensory neurons during the development and maintenance of inflammation. 相似文献
17.
Y Frobert M C Nevers S Amadesi H Volland P Brune P Geppetti J Grassi C Créminon 《Peptides》1999,20(2):275-284
Thirty mouse monoclonal antibodies (mAbs) directed against rat calcitonin gene-related peptide-alpha (CGRP-alpha) have been obtained. These mAbs are classified in 2 groups, one recognizing the peptide N-terminus and the other binding the C-terminus. A two-site immunometric assay was developed using mAb CGRP-83 as capture antibody, whereas mAb CGRP-72 acts as tracer, covalently labeled with enzyme acetylcholinesterase. This assay appeared sensitive (limit of detection: 2 pg/ml) and precise, allowing quantitative measurement of all human and murine CGRP isoforms. The assay was used to determine specific concentrations of CGRP in different rat, mice and guinea pig samples. The validity of the test was demonstrated by HPLC fractionation experiments. 相似文献
18.
Calcitonin gene-related peptide (CGRP) is clearly an anabolic factor in skeletal tissue, but the distribution of CGRP receptor (CGRPR) subtypes in osteoblastic cells is poorly understood. We previously demonstrated that the CGRPR expressed in osteoblastic MG63 cells does not match exactly the known characteristics of the classic subtype 1 receptor (CGRPR1). The aim of the present study was to further characterize the MG63 CGRPR using a selective agonist of the putative CGRPR2, [Cys(Acm)(2,7)]CGRP, and a relatively specific antagonist of CGRPR1, CGRP(8-37). [Cys(Acm)(2,7)]CGRP acted as a significant agonist only upon ERK dephosphorylation, whereas this analog effectively antagonized CGRP-induced cAMP production and phosphorylation of cAMP response element-binding protein (CREB) and p38 MAPK. Although it had no agonistic action when used alone, CGRP(8-37) potently blocked CGRP actions on cAMP, CREB, and p38 MAPK but had less of an effect on ERK. Schild plot analysis of the latter data revealed that the apparent pA2 value for ERK is clearly distinguishable from those of the other three plots as judged using the 95% confidence intervals. Additional assays using 3-isobutyl-1-methylxanthine or the PKA inhibitor N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide hydrochloride (H-89) indicated that the cAMP-dependent pathway was predominantly responsible for CREB phosphorylation, partially involved in ERK dephosphorylation, and not involved in p38 MAPK phosphorylation. Considering previous data from Scatchard analysis of [125I]CGRP binding in connection with these results, these findings suggest that MG63 cells possess two functionally distinct CGRPR subtypes that show almost identical affinity for CGRP but different sensitivity to CGRP analogs: one is best characterized as a variation of CGRPR1, and the second may be a novel variant of CGRPR2. 相似文献
19.
Positive inotropic effects and receptors of calcitonin gene-related peptide (CGRP) in porcine ventricular muscles 总被引:1,自引:0,他引:1
T Miyauchi Y Sano O Hiroshima T Yuzuriha Y Sugishita T Ishikawa A Saito K Goto 《Biochemical and biophysical research communications》1988,155(1):289-294
Calcitonin gene-related peptide (CGRP) in porcine ventricular muscles. positive inotropic effects in the isolated, electrically driven false tendon of the porcine heart. Specific CGRP-binding sites were present in solubilized membrane fractions; the dissociation constant (Kd) and the maximum binding (Bmax) were 50.4 pM and 180 fmol/mg protein, respectively. SDS-PAGE analysis of CGRP-binding sites revealed the molecular mass of 70 K and 120 K. Few CGRP-like immunoreactive nerves were present in the ventricular muscle layer. These results indicate that CGRP activates specific receptor sites on the ventricular muscles and causes positive inotropic responses. CGRP receptors in ventricles are likely to be activated by circulating CGRP. 相似文献
20.
M Zaidi H K Datta T J Chambers I MacIntyre 《Biochemical and biophysical research communications》1989,158(1):214-219
A subclone of an osteoblast-like osteosarcoma cell line (UMR 106.01) has recently been shown to possess specific binding sites for calcitonin gene-related peptide (CGRP) linked to adenylate cyclase. The present study provides the first demonstration for the production of immunoreactive CGRP from CGRP-receptor positive osteosarcoma cells. Mean immunoreactive CGRP levels were 15 pmol/g and 1 pmol/l for acid extracts of cells and cell-exposed media respectively. On gel filtration and high performance liquid chromatography, a major proportion of immunoreactive CGRP was found to co-elute with synthetic rat CGRP(1-37). Only negligible quantities of calcitonin were detected in cell extracts or cell-exposed supernatant. The production of authentic CGRP from a CGRP-receptor positive tumour suggests that the peptide may have autocrine effects on its producer cell. 相似文献