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Author

Michael J. Ryan

Other affiliations: Parke-Davis
Bio: Michael J. Ryan is an academic researcher from Pfizer. The author has contributed to research in topics: Small molecule & Adenosine A1 receptor. The author has an hindex of 10, co-authored 13 publications receiving 571 citations. Previous affiliations of Michael J. Ryan include Parke-Davis.

Papers
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Journal ArticleDOI
TL;DR: A series of renin inhibitors was synthesized that contained a 2-amino-4-thiazolyl moiety at the P2 position that exhibited oral blood pressure lowering activity in high-renin normotensive monkeys and was selected for further evaluation in renal hypertensive monkeys on the basis of its superior efficacy and duration of action.
Abstract: A series of renin inhibitors was synthesized that contained a 2-amino-4-thiazolyl moiety at the P2 position. These derivatives are potent inhibitors of monkey renin in vitro and are selective in that they only weakly inhibit the closely related aspartic proteinase, bovine cathepsin D. Four compounds exhibited oral blood pressure lowering activity in high-renin normotensive monkeys. One of these compounds, 22 (PD 134672), was selected for further evaluation in renal hypertensive monkeys, on the basis of its superior efficacy and duration of action in the in vitro assays and the normotensive primate model.

343 citations

Journal ArticleDOI
TL;DR: Compounds with a 2-methyl-2-aryl substitution pattern exhibit potent renin inhibition and good permeability, solubility, and metabolic stability and oral bioavailability was found to be dependent on metabolic clearance and cellular permeability.

46 citations

Journal ArticleDOI
TL;DR: It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition.

37 citations

Journal ArticleDOI
TL;DR: In this article, a series of novel N6-benzocycloalkyladenosines were studied and their receptor binding and anti-hypertensive activity was investigated.
Abstract: Adenosine is known to exert a wide range of pharmacological effects including hypotension. This effect of adenosine suggested that modified analogues of adenosine might provide useful antihypertensive agents. Thus, we prepared a series of novel N6-benzocycloalkyladenosines and studied their receptor binding and antihypertensive activity. The structure-activity relationship study shows that the adenosine analogues having the hydrophobic phenyl moiety one carbon away from the C6-nitrogen have modest affinity and selectivity for the A1 receptor, whereas those with the phenyl moiety two carbons away from the C6-nitrogen have excellent affinity and selectivity for the A1 receptor. Many of these analogues showed excellent antihypertensive activity with a wide range of effects on heart rate. There is no direct correlation between the receptor binding affinities and antihypertensive activity; however, it is more closely associated with A1 than A2 affinity. The bradycardic effect of these agonists seems to be due to the A1 affinity. From this set, compound 3 was further evaluated in secondary antihypertensive screens. It lowered the blood pressure dose dependently with effects lasting for over 20 h following administration of a 30 mg/kg dose. Compound 3 was also effective in lowering blood pressure in a renal hypertensive rat model. Thus, appropriately modified N6-substituted adenosines represent a novel class of antihypertensive agents.

36 citations

Journal ArticleDOI
TL;DR: While uptake into hepatic cells was rapid regardless of partition coefficient or molecular weight, rate of appearance in bile was dependent on the molecular weight of the compounds, and compounds with higher lipophilicity were better absorbed from the intestine.
Abstract: A series of radiolabeled compounds related to renin inhibitor structures was synthesized to represent a range of physicochemical properties. These compounds were tested in assays for intestinal absorption and hepatic clearance in order to define parameters conducive to optimizing bioavailability. In general, compounds with higher lipophilicity were better absorbed from the intestine. Absorption may also be dependent on molecular charge, as compounds with ionizable functionality were less well-absorbed than neutral compounds. Neutral compounds showed some dependency on molecular weight, with smaller compounds exhibiting better absorption. While uptake into hepatic cells was rapid regardless of partition coefficient or molecular weight, rate of appearance in bile was dependent on the molecular weight of the compounds.

27 citations


Cited by
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Journal ArticleDOI
TL;DR: The alkylation of amines by alcohols has been achieved using 0.5 mol % [Ru(p-cymene)Cl(2)](2) with the bidentate phosphines dppf or DPEphos as the catalyst.
Abstract: The alkylation of amines by alcohols has been achieved using 0.5 mol % [Ru(p-cymene)Cl2]2 with the bidentate phosphines dppf or DPEphos as the catalyst. Primary amines have been converted into secondary amines, and secondary amines into tertiary amines, including the syntheses of Piribedil, Tripelennamine, and Chlorpheniramine. N-Heterocyclization reactions of primary amines are reported, as well as alkylation reactions of primary sulfonamides. Secondary alcohols require more forcing conditions than primary alcohols but are still effective alkylating agents in the presence of this catalyst.

556 citations

Journal ArticleDOI
TL;DR: Various named reactions, multi-component reactions and the synthesis of heterocyclic compounds are discussed including the use of various energy input systems such as microwave- and ultrasound irradiation, among others.
Abstract: Catalyst-free reactions developed during the last decade and the latest developments in this emerging field are summarized with a focus on catalyst-free reactions in-water and on-water. Various named reactions, multi-component reactions and the synthesis of heterocyclic compounds are discussed including the use of various energy input systems such as microwave- and ultrasound irradiation, among others. Organic chemists and the practitioners of this art both in academia and industry hopefully will continue to design benign methodologies for organic synthesis in aqueous media under catalyst-free conditions by using alternative energy inputs based on fundamental principles.

533 citations

Journal ArticleDOI
TL;DR: Dihydropyrimidine 12a is both more potent and longer acting than nifedipine and compares most favorably with the long-acting dihydropyridine derivative amlodipine in vitro and has the potential advantage of being a single enantiomer in vivo.
Abstract: We have examined a series of novel dihydropyrimidine calcium channel blockers that contain a basic group attached to either C5 or N3 of the heterocyclic ring. Structure-activity studies show that a 1-(phenylmethyl)-4-piperidinyl carbamate moiety at N3 and sulfur at C2 are optimal for vasorelaxant activity in vitro and impart potent and long-acting antihypertensive activity in vivo. One of these compounds (11) was identified as a lead, and the individual enantiomers 12a (R) and 12b (S) were synthesized. Two key steps of the synthesis were (1) the efficient separation of the diastereomeric ureido derivatives 29a/29b and (2) the high-yield transformation of 2-methoxy intermediates 30a/30b to the (p-methoxybenzyl)thio intermediates 31a/31b. Chirality was demonstrated to be a significant determinant of biological activity, with the dihydropyridine receptor recognizing the enamino ester moiety (12a) but not the carbamate moiety (12b). Dihydropyrimidine 12a is equipotent to nifedipine and amlodipine in vitro. In the spontaneously hypertensive rat, dihydropyrimidine 12a is both more potent and longer acting than nifedipine and compares most favorably with the long-acting dihydropyridine derivative amlodipine. Dihydropyrimidine 12a has the potential advantage of being a single enantiomer.

412 citations

PatentDOI
26 Dec 2012-Science
TL;DR: The use of chiral cation salts as phase-transfer catalysts for anionic reagents has enabled a vast set of enantioselective transformations as discussed by the authors, such as the fluorocyclization of olefins and dearomatization of aromatic systems with a cationic electrophile transferring (e.g., fluorinating) agent and a chiral phosphate catalyst.
Abstract: The discovery of distinct modes of asymmetric catalysis has the potential to rapidly advance chemists' ability to build enantioenriched molecules. As an example, the use of chiral cation salts as phase-transfer catalysts for anionic reagents has enabled a vast set of enantioselective transformations. A largely overlooked analogous mechanism wherein a chiral anionic catalyst brings a cationic species into solution is itself a powerful method. The concept is broadly applicable to a number of different reaction pathways, including to the enantioselective fluorocyclization of olefins, and dearomatization of aromatic systems with a cationic electrophile-transferring (e.g., fluorinating) agent and a chiral phosphate catalyst. The reactions proceed in high yield and stereoselectivity. The compounds and methods of the invention are of particular value, especially considering the scarcity of alternative approaches.

351 citations