Pharmaceutical biotechnology最新文献_第7页

The discovery and development of angiotensin II antagonists. 血管紧张素II拮抗剂的发现与发展。

Pharmaceutical biotechnology Pub Date : 1998-01-01 DOI: 10.1007/0-306-47384-4_3

D J Carini, D D Christ, J V Duncia, M E Pierce

引用次数: 15

Dorzolamide, a 40-year wait. From an oral to a topical carbonic anhydrase inhibitor for the treatment of glaucoma. 多唑胺，40年的等待。从口服到外用碳酸酐酶抑制剂治疗青光眼。

Pharmaceutical biotechnology Pub Date : 1998-01-01

G S Ponticello, M F Sugrue, B Plazonnet, G Durand-Cavagna

{"title":"Dorzolamide, a 40-year wait. From an oral to a topical carbonic anhydrase inhibitor for the treatment of glaucoma.","authors":"G S Ponticello, M F Sugrue, B Plazonnet, G Durand-Cavagna","doi":"","DOIUrl":"","url":null,"abstract":"Dorzolamide, on the basis of its pharmacological profile and lack of undesirable side effects in safety assessment studies together with the fact that it could be formulated in solution at 2%, underwent extensive clinical studies. Early clinical studies in the development of dorzolamide have been described elsewhere (Maren, 1995; Serle and Podos, 1995). In a 1-year study in which a comparison was undertaken in patients for intraocular pressure lowering effects between 2% dorzolamide administered three times daily, 0.5% betaxolol twice daily, and 0.5% timolol twice daily, the peak reductions in intraocular pressure were 23, 21, and 25%, respectively. Tachyphylaxis did not develop to dorzolamide nor were electrolyte and/or systemic side effects encountered (Strahlman et al., 1995). The latter is consistent with results of a pharmacokinetic study in humans in which plasma levels of dorzolamide were lower than the limit of detection (5 ng/ml) at a time when the red blood cell content of dorzolamide had reached steady state which was appreciably less than the red blood cell content of the enzyme (Biollaz et al., 1995). Patients taking 0.5% timolol twice daily received either 2% dorzolamide twice daily or 2% pilocarpine four times daily for 6 months and the additional reductions in intraocular pressure elicited by dorzolamide and pilocarpine were very similar. However, pilocarpine usage resulted in a higher discontinuation rate (Strahlman et al., 1996). In a separate study in which dorzolamide and pilocarpine were compared at these dosage schedules, patients preferred dorzolamide to pilocarpine by a ratio of over 7 to 1 in terms of quality of life (Laibovitz et al., 1995). In summary, the quest for a topical, ocular hypotensive, CA inhibitor, though time-consuming, was a successful one with the introduction of dorzolamide into general clinical practice.","PeriodicalId":19777,"journal":{"name":"Pharmaceutical biotechnology","volume":"11 ","pages":"555-74"},"PeriodicalIF":0.0,"publicationDate":"1998-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20674263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery and development of an endothelin A receptor-selective antagonist PD 156707. 内皮素A受体选择性拮抗剂PD 156707的发现与开发。

Pharmaceutical biotechnology Pub Date : 1998-01-01 DOI: 10.1007/0-306-47384-4_5

A M Doherty, A C Uprichard

引用次数: 4

Endothelin receptor antagonists. 内皮素受体拮抗剂。

Pharmaceutical biotechnology Pub Date : 1998-01-01 DOI: 10.1007/0-306-47384-4_6

J D Elliott, E H Ohlstein, C E Peishoff, H M Ellens, M A Lago

引用次数: 4

De novo design and discovery of cyclic HIV protease inhibitors capable of displacing the active-site structural water molecule. 重新设计和发现环状HIV蛋白酶抑制剂能够取代活性位点结构水分子。

Pharmaceutical biotechnology Pub Date : 1998-01-01 DOI: 10.1007/0-306-47384-4_12

G V De Lucca, P K Jadhav, R E Waltermire, B J Aungst, S Erickson-Viitanen, P Y Lam

引用次数: 62

Discovery and development of the BHAP nonnucleoside reverse transcriptase inhibitor delavirdine mesylate. BHAP非核苷类逆转录酶抑制剂甲磺酸德拉韦丁的发现与开发。

Pharmaceutical biotechnology Pub Date : 1998-01-01 DOI: 10.1007/0-306-47384-4_13

W J Adams, P A Aristoff, R K Jensen, W Morozowich, D L Romero, W C Schinzer, W G Tarpley, R C Thomas

引用次数: 6

CI-1015. An orally active CCK-B receptor antagonist with an improved pharmacokinetic profile. ci - 1015。一种口服活性CCK-B受体拮抗剂，具有改善的药代动力学特征。

Pharmaceutical biotechnology Pub Date : 1998-01-01

B K Trivedi, J P Hinton

引用次数: 0

Discovery of bioavailable inhibitors of secretory phospholipase A2. 发现生物有效的分泌型磷脂酶A2抑制剂。

Pharmaceutical biotechnology Pub Date : 1998-01-01 DOI: 10.1007/0-306-47384-4_19

S G Blanchard, R C Andrews, P J Brown, L S Gan, F W Lee, A K Sinhababu, T N Wheeler

{"title":"Discovery of bioavailable inhibitors of secretory phospholipase A2.","authors":"S G Blanchard, R C Andrews, P J Brown, L S Gan, F W Lee, A K Sinhababu, T N Wheeler","doi":"10.1007/0-306-47384-4_19","DOIUrl":"https://doi.org/10.1007/0-306-47384-4_19","url":null,"abstract":"Substrate-mimetic inhibitors of sPLA2 with submicromolar in vitro potency were discovered by use of a novel dual substrate screening strategy. In vivo evaluation of selected inhibitors in the rat carrageenan paw edema model of inflammation, however, indicated that in vitro potency was not a good predictor of in vivo activity. Studies of the metabolic stability of early examples of these inhibitors suggested that the metabolic lability of these compounds was a major contributing factor to the observed weak in vivo activity. In an attempt to achieve improved in vivo activity, we prepared and tested compounds designed to overcome the observed metabolic instability. The design of the new compounds involved two types of changes in the inhibitor molecules. First, the C-2 ester moiety was replaced with an amide function so that direct cleavage by stomach acid and blood esterases at this site was minimized. Second, omega-oxidation of the decanamide moiety was eliminated by substitution of hydrogen with fluorine in this position. Compounds containing fluorine in the terminal positions of the alkyl chain retained sPLA2 inhibitory activity and also possessed improved in vitro metabolic stability and pharmacokinetic parameters relative to nonfluorinated inhibitors in this series. As exemplified by GW 4776, improvements in metabolic stability alone, however, were not sufficient to ensure oral activity. Thus, GW 4776 did not show oral activity in the carrageenan edema model and had only modest activity after i.v. dosing in the same model. In fact, the results for GW 9624 and GW 8219 suggested that factors in addition to potency of sPLA2 inhibition and metabolism affect the observed in vivo activity. Despite the fact that these two compounds varied only by a single oxygen-to-sulfur substitution, one was active whereas the other was not. One possible explanation for the observed variability is a compound-dependent difference in the rate of equilibration into tissue. This possibility is relevant as both the carrageenan paw edema model and the phorbol ester edema model involve a localized inflammation. No measurements were made to assess differences in the distribution of the different inhibitors between the blood and the localized site of inflammation. In summary, a series of bioavailable inhibitors of sPLA2 was prepared using an iterative approach that combined medicinal chemistry, in vitro and in vivo evaluation of biological activity, and metabolic and pharmacokinetic studies. Although some compounds in the series showed in vivo activity, the anti-inflammatory effect observed in animal models was modest and a decision was made to abandon sPLA2 as a molecular target for the development of anti-inflammatory agents.","PeriodicalId":19777,"journal":{"name":"Pharmaceutical biotechnology","volume":"11 ","pages":"445-63"},"PeriodicalIF":0.0,"publicationDate":"1998-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1007/0-306-47384-4_19","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20673643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 12

The anxieties of drug discovery and development. CCK-B receptor antagonists. 药物发现和开发的焦虑。CCK-B受体拮抗剂。

Pharmaceutical biotechnology Pub Date : 1998-01-01 DOI: 10.1007/0-306-47384-4_20

F Lombardo, S M Winter, L Tremaine, J A Lowe

引用次数: 3

LHRH antagonists.

Pharmaceutical biotechnology Pub Date : 1998-01-01 DOI: 10.1007/978-3-642-16483-5_6837

F. Haviv, E. Bush, J. Knittle, J. Greer

引用次数: 11