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Fintan Kelleher

Other affiliations: Trinity College, Dublin, Merck & Co.
Bio: Fintan Kelleher is an academic researcher from Institute of Technology, Tallaght. The author has contributed to research in topics: Tetrazole & Pyridine. The author has an hindex of 15, co-authored 45 publications receiving 599 citations. Previous affiliations of Fintan Kelleher include Trinity College, Dublin & Merck & Co..

Papers
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Journal ArticleDOI
TL;DR: The identification of oxazolidinedione 14 as a suitable ester mimic in terms of the retention of good NK1 binding affinity is identified.
Abstract: The 3,5-bis(trifluoromethyl)benzyl ester of N-acetyl-L-tryptophan 1 (L-732,138) has been identified previously as a potent and selective substance P receptor antagonist. A series of analogs which introduced a 6-membered heterocyclic ring into the backbone of this structure were prepared for evaluation as bioisosteric replacements of the ester linkage of 1. The 2,5-dioxopiperazine 2 had very weak receptor affinity, but 2-oxopiperazine 5 exhibited modest activity. Examination of the conformations accessible to the substituents on these templates led to exploration of the corresponding 5-membered heterocyclic rings. This study culminated in the identification of oxazolidinedione 14 as a suitable ester mimic in terms of the retention of good NK1 binding affinity.

62 citations

Journal ArticleDOI
TL;DR: 3,5-bis-(trifluoromethyl)benzyl ester of N-acetyl-L-tryptophan 26 was the most potent compound from this structurally novel class of antagonists which further adds to the diversity of small molecules that bind to the (NK1) receptor.
Abstract: As part of a program of screening the Merck sample collection, N-ethyl-L-tryptophan benzyl ester was identified as a weak antagonist at the substance P (NK1) receptor. Structure-activity studies showed that the indole ring system could be replaced by 3,4-dichlorophenyl, alpha- or beta-naphthyl, or benzthiophene with retention or only small loss of affinity. It was found that acylation of the tryptophan nitrogen gave compounds with higher affinity than N-ethyl or other basic amines. Optimization of substitution on the benzyl ester led to the identification of the 3,5-bis-(trifluoromethyl)benzyl ester of N-acetyl-L-tryptophan 26 as a potent and selective substance P receptor antagonist. Compound 26 blocked substance P induced dermal extravasation in vivo and was the most potent compound from this structurally novel class of antagonists which further adds to the diversity of small molecules that bind to the (NK1) receptor.

57 citations

Journal ArticleDOI
TL;DR: In this article, a series of high-affinity NK1 antagonists based on the 4,4-disubstituted piperidine ring system were designed for in vivo study in the resiniferotoxin-induced vascular leakage model.
Abstract: Previously reported studies from these laboratories described the design of a novel series of high-affinity NK1 antagonists based on the 4,4-disubstituted piperidine ring system. Further structure−activity studies have now established that for high NK1 affinity the benzyl ether side chain must be 3,5-disubstituted and highly lipophilic, the optimal side chain being the 3,5-bis(trifluoromethyl)benzyl ether, 12 (hNK1 IC50 = 0.95 nM). Additional studies have shown that this class of NK1 antagonist tolerates a wider range of substituents on the piperidine nitrogen, including acyl (38) (hNK1 IC50 = 5.3 nM) and sulfonyl (39) (hNK1 IC50 = 5.7 nM) derivatives. Following preliminary pharmacokinetic analysis, two compounds (32 and 43) were selected for in vivo study in the resiniferotoxin-induced vascular leakage model, both showing excellent profiles (ID50 = 0.22 and 0.28 mg/kg, respectively).

42 citations

Patent
15 Feb 1994
TL;DR: In this article, the present invention relates to compounds of formula (I) and salts and prodrugs thereof, wherein Q 1 represents a phenyl group substituted by one or more halo optionally substituted naphthyl, optionally substituted indolyl, etc.
Abstract: The present invention relates to compounds of formula (I) and salts and prodrugs thereof, wherein Q 1 represents a phenyl group substituted by one or more halo optionally substituted naphthyl, optionally substituted indolyl, optionally substituted benzthiophenyl, optionally substituted benzofuranyl, optionally substituted benzyl or optionally substituted fluorenyl; R 1 represents H or C 1-6 alkyl; R 2 represents H, C 1-6 alkyl or C 2-6 alkenyl; Z 1 represents a group selected from (a) or (b). The compounds are tachykinin antagonists useful for treating pain or inflammation, migraine or emesis.

38 citations

Journal ArticleDOI
TL;DR: In this article, the crystal structures of both 1,2]-(2-vinyl)tetrazol-5-yl]benzene (1-N,2-N′) ( 1b ) and 1,3-bis[(2bromoethyl)tetrabromoethyltetrazolate-5yl]bensene (2-n,2)-n′)( 5d ) are discussed.

30 citations


Cited by
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Journal ArticleDOI
TL;DR: Privileged substructures are believed to achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns.
Abstract: Privileged substructures are of potentially great importance in medicinal chemistry. These scaffolds are characterized by their ability to promiscuously bind to a multitude of receptors through a variety of favorable characteristics. This may include presentation of their substituents in a spatially defined manner and perhaps also the ability to directly bind to the receptor itself, as well as exhibiting promising characteristics to aid bioavailability of the overall molecule. It is believed that some privileged substructures achieve this through the mimicry of common protein surface elements that are responsible for binding, such as β- and gamma;-turns. As a result, these structures represent a promising means by which new lead compounds may be identified.

2,620 citations

Journal ArticleDOI
TL;DR: This topic has been reviewed in previous years and the objective of this review is to provide an overview of bioisosteres that incorporates sufficient detail to enable the reader to understand the concepts being delineated.
Abstract: Years of cumulative research can result in the development of a clinically useful drug, providing either a cure for a particular disease or symptomatic relief from a physiological disorder. A lead compound with a desired pharmacological activity may have associated with it undesirable side effects, characteristics that limit its bioavailability, or structural features which adversely influence its metabolism and excretion from the body. Bioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents. The concept of bioisosterism is often considered to be qualitative and intuitive.1 The prevalence of the use of bioisosteric replacements in drug design need not be emphasized. This topic has been reviewed in previous years.2-5 The objective of this review is to provide an overview of bioisosteres that incorporates sufficient detail to enable the reader to understand the concepts being delineated. While a few popular examples of the successful use of bioisosteres have been included, the George Patani graduated with a B.Pharm. in 1992 from the College of Pharmaceutical Sciences, Mangalore University at Manipal, India. In 1996, he received his M.S. in Pharmaceutical Science at Rutgers University under the direction of Professor Edmond J. LaVoie. He is presently pursuing graduate studies in pharmaceutics. His current research interests are focused on drug design and controlled drug delivery.

2,277 citations

Journal ArticleDOI
TL;DR: This review concludes that Etherification without Cyclization and N-Alkylation should be considered as separate science, and the proposed treatment of Etherification with Cyclization as a separate science should be reconsidered.
Abstract: 10. Patented Literature 2616 10.1. Esterification 2616 10.2. Ether Formation 2619 10.2.1. Etherification without Cyclization 2619 10.2.2. Etherification with Cyclization 2624 10.3. N-Alkylation 2625 10.4. Other Reactions 2627 11. Summary and Outlook 2628 12. Note Added in Proof 2628 13. Abbreviations Used in This Review 2629 14. Acknowledgments 2629 15. Supporting Information Available 2630 16. References 2630

909 citations

Patent
05 Apr 2005
TL;DR: In this article, the use of heterocyclic carboxamide compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis was discussed, and the authors proposed a method to synthesize carboxamides for use as inhibitors.
Abstract: Invented are novel heterocyclic carboxamide compounds, the use of such compounds as inhibitors of protein kinase B activity and in the treatment of cancer and arthritis

566 citations

01 Jan 2016
TL;DR: The Methods in Molecular Biology series was the first to introduce the step-by-step protocols approach that has become the standard in all biomedical protocol publishing and is indexed in PubMed.
Abstract: For over 35 years, biological scientists have come to rely on the research protocols and methodologies in the critically acclaimed Methods in Molecular Biology series. The series was the first to introduce the step-by-step protocols approach that has become the standard in all biomedical protocol publishing. Each protocol is provided in readilyreproducible step-bystep fashion, opening with an introductory overview, a list of the materials and reagents needed to complete the experiment, and followed by a detailed procedure that is supported with a helpful notes section offering tips and tricks of the trade as well as troubleshooting advice. These hallmark features were introduced by series editor Dr. John Walker and constitute the key ingredient in each and every volume of the Methods in Molecular Biology series. Tested and trusted, comprehensive and reliable, all protocols from the series are indexed in PubMed.

388 citations