Parke Davis inhibitors

Several pathological self-polymerizing systems have been biophysi-cally characterized sufficiently to permit identification of protein or peptide species that could serve as molecular targets in a structure-activity relationship. These include transthyretin (TTR) [73-76], serum amyloid A protein (SAA) [77], microtubule-associated protein tau [78-80], amylin or islet amyloid polypeptide (IAPP) [81,82], IgG light chain amyloidosis (AL) [83-85], polyglutamine diseases [9,86], a-synuclein [47,48] and the Alzheimer s (3 peptide [87-96]. A variety of A(3 peptide assay systems have been established at Parke-Davis to search for inhibitors of fibril formation that could be therapeutically useful [97]. 

The initial pyrido[2,3-d]pyrimidines were first reported as Src inhibitors by Parke-Davis, now Pfizer, and the first disclosures of Abl activity were done in collaboration with academic researchers. Although the recent studies with these analogs were reported by academic groups, it has been stated that Sloan-Kettering is working with a pharmaceutical company to develop a compoimd from this class [92]. 

Fostriecin (20, CI-920) is a novel metabolite of Streptomyces pulveraceus that was first isolated in 1983 by a research group at Warner Lambert-Parke Davis.22 It displays antitumor activity against a broad range of cancerous cell lines in vitro. This activity is suggested to be intimately related to the potent and highly selective inhibitory activity against serine/threonine phosphatase PP2A.23 In fact, fostriecin is the most selective protein phosphatase inhibitor reported to date, and it... 

A group at Parke-Davis reported the preparation of 5-deazaAP (80a) in 1974 [74,75], This was the first synthesis of a member of this class of DHFR inhibitor. As shown in Scheme 3.16, the key intermediate, 2,4-diamino-5-deazapteridine-6-carbonitrile (79), was constructed in a straightforward manner in five steps from malononitrile. The use of chloroformamidine for the conversion of (78) to (79) proved to be less satisfactory than the (traditional) use of guanidine. 

Figure 2.21 The achiral 4-hydroxypyrone 77 (K, = 10 pM) is structurally related to anticoagulant vitamin K antagonists it was discovered at Parke-Davis as a weakly active lead in a screening for HIV protease inhibitors. Optimization produced the thio ether 78 (K, = 35 nM) and finally CI-1029, 79 (K, = 0.11 nM). In an independent screening, Upjohn discovered that the therapeutically used anticoagulant phenprocoumon 80 (K, = 1 pM) is a weak HIV protease inhibitor. Optimization at Pharmacia and Upjohn produced PNU-96 988, 81 ( ) = 38 nM), and the pico-molar HIV protease inhibitor tipranavir 82 (R,R diastereomer K = 8 pM).

Agents that can inhibit more than one inflammatory mediator may be advantageous. Compounds that inhibit both COX-2 and 5-LO may have an efficacy advantage over current agents in the treatment of rheumatoid arthritis. Parke-Davis has reported Cl-1004, dar-bufelone (98), and PD 138387 (97) as dual 5-LO/COX-2 inhibitors (402). Darbufelone was reported to be in clinical trials and has recently been described in detail (402). PD-... 

Both Parke-Davis and Upjohn researchers have identified warfarin and its analogue as weak inhibitors of HIV protease.9,32 Furthermore, Bour-inbaiar et al.47,48 have also reported that warfarin possessed an antiviral effect on HIV replication and spread, but it was unclear if this antiviral... 

Accuretic Acequide Koretic Quinapril Quinaprilum. component of Accuretic Acequide Koretic. Angiotensin-converting enzyme inhibitor. Orally active peptidyl-dipeptide hydrolase inhibitor. Antihypertensive. Parke-Davis. 

Selective COX-2 inhibitors Mass screening of the Parke-Davis library for compounds that would inhibit COX-2 identified original hits derived from 2,6-di-tert-butylphenol (generic structures I and II , Fig. 5.11). These compounds are related to probucol and are totally different from the previously reported selective COX-2 inhibitors. ... 

Several non-peptide small molecule compoimds from Merck, Schering-Plough, Bristol-Myers Squibb, and Janssen are in phase I clinical trials for the treatment of cancer. This has bolstered the significance of this approach of cancer chemotherapy. Other organizations that have ongoing active FPTase inhibitor programs include Abbott, Rhone Poulenc Rorer, Parke- Davis, Pfizer, Zeneca, Eisai and Biomeasure. While several review articles have recently been published that cover various aspects of FPTase inhibitors [25-28,31,60,61], the discussion of FPTase inhibitors derived from natural products is limited. Therefore, this article will not be an extensive review of the literature dealing with chemically derived inhibitors of farnesyl-protein transferase. Rather, it will focus on inhibitors of famesyl-protein transferase that have been identified from natural product sources discovered by Merck or other institutions. 

PBL (peripheral blood lymphocytes) isoquinolinon PARP inhibitors from Parke Davis (ICO 2250 and ICD2163) Sulfur mustard 51... 

At the time the ester 173 was disclosed, a demand came for stereoselective acetate aldol reactions in the development of HMG-CoA reductase inhibitors, which feature unbranched p,8-dihydroxy carboxylic acids or the corresponding 8-lactones as the pharmacophore. Thus, a series of those inhibitors were synthesized, partly in large scale, by using the HYTR A method [99], and some of them made it to best-selling drugs like atorvastatin [99a-d], fluvastatin [99e, f], and lovastatin [99g] that were developed by the companies Parke-Davis, Sandoz, and Merck, respectively (Scheme 4.38). 

Pang, Y.P., Vummenthala, A., Mishra, R.K., Park, J.G., Wang, S., Davis, J., Millard, C.B., and Schmidt, J.J. (2009) Potent new small-molecule inhibitor of botulinum neurotoxin serotype A endopeptidase developed by synthesis-based computer-aided molecular design. PLoS One, 4, e7730. 

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