共查询到20条相似文献,搜索用时 15 毫秒
1.
Mark Hadden Allan Goodman Cheng Guo Peter R. Guzzo Alan J. Henderson Kevin Pattamana Megan Ruenz Bruce J. Sargent Brian Swenson Larry Yet Jian Liu Shuwen He Iyassu K. Sebhat Linus S. Lin Constantin Tamvakopoulos Qianping Peng Yanqing Kan Oksana Palyha Theresa M. Kelly Xiao-Ming Guan Ravi P. Nargund 《Bioorganic & medicinal chemistry letters》2010,20(9):2912-2915
SAR around non-peptidic potent bombesin receptor subtype-3 (BRS-3) agonist lead 2 is presented. Attempts to replace the carboxylic acid with heterocyclic isosteres to improve oral bioavailability and brain penetration are described. 相似文献
2.
Lo MM Chobanian HR Palyha O Kan Y Kelly TM Guan XM Reitman ML Dragovic J Lyons KA Nargund RP Lin LS 《Bioorganic & medicinal chemistry letters》2011,21(7):2040-2043
Bombesin receptor subtype-3 (BRS-3) is an orphan G-protein coupled receptor belonging to the subfamily of bombesin-like receptors. BRS-3 is implicated in the development of obesity and diabetes. We report here small-molecule agonists that are based on a 4-(alkylamino)pyridine-3-sulfonamide core. We describe the discovery of 2a, which has mid-nanomolar potency, selectivity for human BRS-3 versus the other bombesin-like receptors, and good bioavailability. 相似文献
3.
《Bioorganic & medicinal chemistry letters》2014,24(3):750-755
The discovery and optimization of a novel series of BRS-3 agonists are described. We explored a potent BRS-3 agonist with low brain penetration to avoid an adverse effect derived from central nervous system exposure. Through the derivatization process, chiral diazepines 9f and 9g were identified as possessing low brain penetration as well as potent in vitro activity against human and mouse BRS-3s. 相似文献
4.
Liu J Lao ZJ Zhang J Schaeffer MT Jiang MM Guan XM Van der Ploeg LH Fong TM 《Biochemistry》2002,41(28):8954-8960
We cloned the gene and cDNA for rat bombesin receptor subtype-3 (BRS-3) and characterized its mRNA expression pattern and pharmacological properties. Despite the high degree of sequence similarity (80% identical), rat and human BRS-3 differ markedly in their pharmacological properties. Although the natural ligand for BRS-3 is still unknown, a synthetic peptide, dY-Q-W-A-V-(beta-A)-H-F-Nle-amide (dY-bombesin), activates human BRS-3 with an EC(50) of 1.2 nM. In contrast, dY-bombesin had a very poor potency for rat BRS-3 (EC(50) = 2 microM). To understand the molecular basis of this pharmacological difference, we constructed chimeric receptors in which individual extracellular loops of rat BRS-3 were replaced with the corresponding human sequences. Switching the N-terminal region or the second extracellular loop did not significantly change receptor properties. However, switching the third extracellular loop (E3) in the rat BRS-3 resulted in a chimeric receptor (RB3-E3) that behaved almost identically to human BRS-3. RB3-E3 bound dY-bombesin with high affinity (K(i) = 1.2 +/- 0.7 nM), and was activated by dY-bombesin with high potency (EC(50) = 1.8 +/- 0.5 nM). Within the E3 loop, mutation of Y(298)E(299)S(300) to S(298)Q(299)T(300) (RB3-SQT) or of D(306)V(307)P(308) to A(306)M(307)H(308) (RB3-AMH) only partially mimicked the effect of switching the entire E3 loop, and mutation of A(302)E(303) to V(302)D(303) or of V(310)V(311) to I(310)F(311) had little effect on the dY-bombesin potency. These results indicate that the sequence variation in the E3 loop is responsible for the species difference between rat and human BRS-3, and multiple residues in the E3 loop are involved in interactions with the agonist dY-bombesin. 相似文献
5.
Carlton DL Collin-Smith LJ Daniels AJ Deaton DN Goetz AS Laudeman CP Littleton TR Musso DL Morgan RJ Szewczyk JR Zhang C 《Bioorganic & medicinal chemistry letters》2008,18(20):5451-5455
Starting from a weak omeprazole screening hit, replacement of the pyridine with a 1,3-benzodioxole moiety, modification of the thioether linkage, and substitution of the benzimidazole pharmacophore led to the discovery of nanomolar BRS-3 agonists. 相似文献
6.
Shuwen He Peter H. Dobbelaar Jian Liu Tianying Jian Iyassu K. Sebhat Linus S. Lin Allan Goodman Cheng Guo Peter R. Guzzo Mark Hadden Alan J. Henderson Megan Ruenz Bruce J. Sargent Larry Yet Theresa M. Kelly Oksana Palyha Yanqing Kan Jie Pan Howard Chen Donald J. Marsh Ravi P. Nargund 《Bioorganic & medicinal chemistry letters》2010,20(6):1913-1917
We report SAR studies on a novel non-peptidic bombesin receptor subtype-3 (BRS-3) agonist lead series derived from high-throughput screening hit RY-337. This effort led to the discovery of compound 22e with significantly improved potency at both rodent and human BRS-3. 相似文献
7.
Smith BM Smith JM Tsai JH Schultz JA Gilson CA Estrada SA Chen RR Park DM Prieto EB Gallardo CS Sengupta D Thomsen WJ Saldana HR Whelan KT Menzaghi F Webb RR Beeley NR 《Bioorganic & medicinal chemistry letters》2005,15(5):1467-1470
We report on the synthesis, biological evaluation and structure-activity relationships for a series of 3-benzazepine derivatives as 5-HT(2C) receptor agonists. The compounds were evaluated in functional assays measuring [3H] phosphoinositol turnover in HEK-293 cells transiently transfected with h5-HT(2C), h5-HT(2A) or h5-HT(2B) receptors. Several compounds are shown to be potent and selective 5-HT(2C) receptor agonists, which decrease food intake in a rat feeding model. 相似文献
8.
Li Zhang Hans-Peter Nothacker Laura M. Bohn Olivier Civelli 《Biochemical and biophysical research communications》2009,387(2):283-288
Bombesin receptor subtype-3 (BRS-3) is an orphan G protein-coupled receptor in the bombesin receptor family that still awaits identification of its natural ligand. BRS-3 deficient mice develop a mild late-onset obesity with metabolic defects, implicating BRS-3 plays a role in feeding and metabolism. We describe here the pharmacological characterization of a synthetic compound, 16a, which serves as a potent agonist for BRS-3. This compound is selective for BRS-3 as it does not activate neuromedin B or gastrin-releasing peptide receptors, two most closely related bombesin receptors, as well as a series of other GPCRs. We assessed the receptor trafficking of BRS-3 and found that compound 16a promoted β-arrestin translocation to the cell membrane. Neither central nor peripheral administration of compound 16a affects locomotor activity in mice. Therefore compound 16a is a potential tool to study the function of the BRS-3 system in vitro and possibly in vivo. 相似文献
9.
Chobanian HR Guo Y Liu P Lanza TJ Chioda M Chang L Kelly TM Kan Y Palyha O Guan XM Marsh DJ Metzger JM Raustad K Wang SP Strack AM Gorski JN Miller R Pang J Lyons K Dragovic J Ning JG Schafer WA Welch CJ Gong X Gao YD Hornak V Reitman ML Nargund RP Lin LS 《Bioorganic & medicinal chemistry》2012,20(9):2845-2849
Bombesin receptor subtype 3 (BRS-3) is an orphan G-protein coupled receptor expressed primarily in the hypothalamus which plays a role in the onset of both diabetes and obesity. We report herein our progress made towards identifying a potent, selective bombesin receptor subtype-3 (BRS-3) agonist related to the previously described MK-7725(1) Chobanian et al. (2012) that would prevent atropisomerization through the increase of steric bulk at the C-2 position. This would thereby make clinical development of this class of compounds more cost effective by inhibiting racemization which can occur over long periods of time at room/elevated temperature. 相似文献
10.
Palucki BL Park MK Nargund RP Tang R MacNeil T Weinberg DH Vongs A Rosenblum CI Doss GA Miller RR Stearns RA Peng Q Tamvakopoulos C Van der Ploeg LH Patchett AA 《Bioorganic & medicinal chemistry letters》2005,15(8):1993-1996
We report the discovery and optimization of substituted 2-piperazinecarboxamides as potent and selective agonists of the melanocortin subtype-4 receptor. The 5- and 6-alkylated piperazine compounds exhibit low bioactivation potential as measured by covalent binding in microsome preparations. 相似文献
11.
Palin R Barn DR Clark JK Cottney JE Cowley PM Crockatt M Evans L Feilden H Goodwin RR Griekspoor F Grove SJ Houghton AK Jones PS Morphy RJ Smith AR Sundaram H Vrolijk D Weston MA Wishart G Wren P 《Bioorganic & medicinal chemistry letters》2005,15(3):589-593
A series of 3-phenoxypropyl piperidine analogues have been discovered as novel ORL1 receptor agonists. Structure-activity relationships have been explored around the 3-phenoxypropyl region with several potent and selective analogues identified. 相似文献
12.
Mark R. Herbert Dana L. Siegel Lena Staszewski Charmagne Cayanan Urmi Banerjee Sangeeta Dhamija Jennifer Anderson Amy Fan Li Wang Peter Rix Andrew K. Shiau Tadimeti S. Rao Stewart A. Noble Richard A. Heyman Eric Bischoff Mausumee Guha Ayman Kabakibi Anthony B. Pinkerton 《Bioorganic & medicinal chemistry letters》2010,20(19):5718-5721
Optimization of a screening hit from uHTS led to the discovery of TGR5 agonist 32, which was shown to have activity in a rodent model for diabetes. 相似文献
13.
K Hotta Y Matsukawa M Nishida K Kotani M Takahashi H Kuriyama T Nakamura K Wada S Yamashita T Funahashi Y Matsuzawa 《Hormones et métabolisme》2000,32(1):33-34
Bombesin receptor subtype-3 (BRS-3) is one of the candidate genes of obesity. The mice lacking BRS-3 have been shown to develop mild obesity. These mice also showed hypertension and impaired glucose metabolism, supporting these mice as a good model for human obesity. We screened 104 Japanese obese men (BMI > 26.4, 26.5-44.1) to investigate whether there is any genetic defect in BRS-3 gene. The DNA fragments containing each exon of BRS-3 gene were amplified by polymerase chain reaction (PCR) and were directly sequenced. No mutation, nor polymorphism was found in the coding region of BRS-3, suggesting that mutation of this gene is not a major cause of obesity in humans. 相似文献
14.
Bentley JM Adams DR Bebbington D Benwell KR Bickerdike MJ Davidson JE Dawson CE Dourish CT Duncton MA Gaur S George AR Giles PR Hamlyn RJ Kennett GA Knight AR Malcolm CS Mansell HL Misra A Monck NJ Pratt RM Quirk K Roffey JR Vickers SP Cliffe IA 《Bioorganic & medicinal chemistry letters》2004,14(9):2367-2370
A series of 1-(1-indolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for all of the compounds at 5-HT(2) receptor subtypes are reported. A number of compounds were found to reduce food intake in rats after oral administration. 相似文献
15.
Chun MW Choi SW Kang TK Choi WJ Kim HO Gao ZG Jacobson KA Jeong LS 《Nucleosides, nucleotides & nucleic acids》2008,27(4):408-420
On the basis of high binding affinity of 3'-aminoadenosine derivatives 2b at the human A3 adenosine receptor (AR), 3'-acetamidoadenosine derivatives 3a-e were synthesized from 1,2:5,6-di-O-isopropylidene-D-glucose via stereoselective hydroboration as a key step. Although all synthesized compounds were totally devoid of binding affinity at the human A3AR, our results revealed that 3'-position of adenosine can only be tolerated with small size of a hydrogen bonding donor like hydroxyl or amino group in the binding site of human A3AR. 相似文献
16.
Cheng Guo Peter R. Guzzo Mark Hadden Bruce J. Sargent Larry Yet Yanqing Kan Oksana Palyha Theresa M. Kelly Xiaoming Guan Kim Rosko Karen Gagen Joseph M. Metzger Jasminka Dragovic Kathryn Lyons Linus S. Lin Ravi P. Nargund 《Bioorganic & medicinal chemistry letters》2010,20(9):2785-2789
The original structure of a high-throughput screening hit obtained from an external vendor was revised based on multiple NMR studies. The active compound was re-synthesized via a novel route and its structure and biological activity as a BRS-3 agonist were unambiguously confirmed. Multi-gram quantities of the hit were prepared for pharmacokinetic and efficacy studies. The synthetic strategy allowed for the preparation of multiple analogs for SAR exploration. 相似文献
17.
Zhou C Guo L Morriello G Pasternak A Pan Y Rohrer SP Birzin ET Huskey SE Jacks T Schleim KD Cheng K Schaeffer JM Patchett AA Yang L 《Bioorganic & medicinal chemistry letters》2001,11(3):415-417
N-Substituted nipecotic and iso-nipecotic amides of beta-methylTrpLys tert-butyl ester were found to be novel, selective and potent agonists of the somatostatin subtype-2 receptor in vitro. For example iso-nipecotic amide 8a showed high hsst2 binding affinity (Ki = 0.5 nM) and good selectivity (h5/h2 = 832). 相似文献
18.
Imanishi N Iwaoka K Koshio H Nagashima SY Kazuta K Ohta M Sakamoto S Ito H Akuzawa S Kiso T Tsukamoto S Mase T 《Bioorganic & medicinal chemistry》2003,11(7):1493-1502
The syntheses and biological evaluation of a series of novel indeno[1,2-d]thiazole derivatives are described. Several groups reported 5-HT(3) receptor agonists which were mainly evaluated for their activities on the von Bezold-Jarisch reflex (B-J reflex). We discovered that tetrahydrothiazolopyridine derivative 1b had a contractile effect on the isolated guinea pig colon with weak B-J reflex. Our efforts to find a new type of 5-HT(3) receptor agonists on the isolated guinea pig colon focused on the synthesis of a fused thiazole derivative 1d modified from 1b and reverse-fused thiazole derivatives (7-10). In this series, 10f (YM-31636) showed high affinity and selectivity for the cloned human 5-HT(3) receptor; furthermore, it showed potent and selective 5-HT(3) receptor agonistic activity. YM-31636 was examined for its effects on defecation in animals, thus evaluating the compound as an agent against constipation. 相似文献
19.
Kher S Lake K Sircar I Pannala M Bakir F Zapf J Xu K Zhang SH Liu J Morera L Sakurai N Jack R Cheng JF 《Bioorganic & medicinal chemistry letters》2007,17(16):4442-4446
Structure-activity relationship studies on a series of Boc-indole derivatives as LXR agonists are described. Compound 1 was identified as an LXR agonist through structure-based virtual screening followed by high-throughput gene profiling. Replacement of the indan linker portion in 1 with an open-chain linker resulted in compounds with similar or improved in vitro potency and cellular functional activity. The Boc group at the N-1 position of the indole moiety can be replaced with a benzoyl group. The SAR studies led to the identification of compound 8, a potent LXRbeta agonist with an EC50 of 12 nM in the cofactor recruitment assay. 相似文献
20.
Ghotas Evindar Sylvie G. Bernier Malcolm J. Kavarana Elisabeth Doyle Jeanine Lorusso Michael S. Kelley Keith Halley Amy Hutchings Albion D. Wright Ashis K. Saha Gerhard Hannig Barry A. Morgan William F. Westlin 《Bioorganic & medicinal chemistry letters》2009,19(2):369-372
In the design of potent and selective sphingosine-1-phosphate receptor agonists, we were able to identify two series of molecules based on phenylamide and phenylimidazole analogs of FTY-720. Several designed molecules in these scaffolds have demonstrated selectivity for S1P receptor subtype 1 versus 3 and excellent in vivo activity in mouse. Two molecules PPI-4621 (4b) and PPI-4691 (10a), demonstrated dose responsive lymphopenia, when administered orally. 相似文献