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1.
Org Lett ; 3(23): 3715-8, 2001 Nov 15.
Article in English | MEDLINE | ID: mdl-11700120

ABSTRACT

[reaction--see text] The semisynthetic conversion of nodulisporic acid A (1) into a set of three heterocyclic side chain derivatives provided compounds, highlighted by 6, with an improved spectrum of ectoparasiticidal activity and pharmacokinetic profile relative to the natural product.


Subject(s)
Indoles/chemical synthesis , Insecticides/chemical synthesis , Oxazoles/chemical synthesis , Thiazoles/chemical synthesis , Animals , Siphonaptera , Ticks
2.
J Parasitol ; 87(5): 1150-4, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11695382

ABSTRACT

Nodulisporic acid A (NSA) has been shown previously to be safe in dogs and to deliver >90% flea control for 4 days following a single oral administration. Three newly prepared nodulisporamide derivatives were subsequently identified from an artificial membrane flea feeding system as exhibiting potency substantially greater than NSA. To determine if they have superior in vivo activity, these 3 nodulisporamides, as well as NSA, were evaluated in dogs at 15 mg/kg/os. Parasite challenges were made by placing 100 live Ctenocephalides felis fleas onto the dorsum of dogs every 48 hr and examining efficacy at each of those intervals over a 22-day period. Results showed that NSA produced >90% efficacy at day 2 and 81% efficacy at day 4, and its residual flea killing fell to approximately 50% by day 6 posttreatment. All dogs treated with the 3 new experimental nodulisporamides were 100% protected from flea challenges to day 8 posttreatment, and 2 of the compounds continued to produce >90% residual activity to 2 wk posttreatment. Pharmacokinetic analysis showed that plasma profiles and half-lives of NSA and these 3 new compounds correlated closely with flea efficacy. These results demonstrate that specific substitutions to the pharmacophore of NSA can substantially increase the duration of activity against fleas.


Subject(s)
Dog Diseases/parasitology , Indoles/pharmacology , Insecticides/pharmacology , Siphonaptera , Administration, Oral , Amides/blood , Amides/pharmacokinetics , Amides/pharmacology , Animals , Dog Diseases/drug therapy , Dog Diseases/metabolism , Dogs , Half-Life , Indoles/blood , Indoles/pharmacokinetics , Insecticides/blood , Insecticides/pharmacokinetics , Male , Random Allocation
3.
Bioorg Med Chem Lett ; 11(8): 1073-6, 2001 Apr 23.
Article in English | MEDLINE | ID: mdl-11327593

ABSTRACT

A series of 2-(3,5-dimethylphenyl)tryptamine derivatives was prepared and evaluated on a rat gonadotropin releasing hormone receptor assay. Some para-substituents on the 4-phenylbutyl side chain attached to the tryptamine nitrogen led to compounds with potent GnRH receptor binding. The study has helped define structural requirements for GnRH receptor binding for the 2-aryltryptamine GnRH antagonists.


Subject(s)
Hormone Antagonists/metabolism , Hormone Antagonists/pharmacology , Receptors, LHRH/metabolism , Tryptamines/chemical synthesis , Tryptamines/metabolism , Tryptamines/pharmacology , Animals , Binding Sites/physiology , Drug Design , Female , Hormone Antagonists/chemistry , Humans , Inhibitory Concentration 50 , Molecular Structure , Rats , Tryptamines/chemistry
4.
Bioorg Med Chem Lett ; 11(8): 1077-80, 2001 Apr 23.
Article in English | MEDLINE | ID: mdl-11327594

ABSTRACT

A series of heterocyclic 2-(3,5-dimethylphenyl)tryptamine derivatives was prepared and evaluated on a rat gonadotropin releasing hormone receptor assay. The carbon tether length and heterocyclic ring attached to the amino group of 2-(3,5-dimethylphenyl)tryptamine were varied. Several of these derivatives were potent GnRH antagonists with the most potent compound having an IC50 of 16 nM.


Subject(s)
Heterocyclic Compounds/chemical synthesis , Hormone Antagonists/metabolism , Receptors, LHRH/metabolism , Tryptamines/chemical synthesis , Tryptamines/metabolism , Animals , Binding Sites/physiology , Drug Design , Female , Hormone Antagonists/chemistry , Inhibitory Concentration 50 , Rats
5.
J Med Chem ; 44(6): 917-22, 2001 Mar 15.
Article in English | MEDLINE | ID: mdl-11300873

ABSTRACT

Extensive development of the structure-activity relationships of a screening lead determined three important pharmacophores for gonadotropin-releasing hormone (GnRH) receptor antagonist activity. Incorporation of the 3,4,5-trimethylphenyl group at the 3-position, 2-(2(S)-azetidinyl)ethoxy group at the 4-position, and N-4-pyrimidinylcarboxamide at the 6-position of the quinolone core resulted in the identification of 4-(2-(azetidin-2(S)-yl)ethoxy)-7-chloro-2-oxo-3-(3,4,5-trimethylphenyl)-1,2-dihydroquinoline-6-carboxylic acid pyrimidin-4-ylamide (1) as a potent antagonist of the GnRH receptor. A 10(4)-fold increase in in vitro binding affinity is observed for the GnRH receptor as compared to the initial screening lead. Compound 1 exhibits nanomolar binding activity and functional antagonism at the human receptor and is 7-fold less active at the rhesus receptor. Intravenous administration of compound 1 to rhesus monkeys results in a significant decrease of the serum levels of downstream hormones, luteinizing hormone (79% decrease in area under the curve) and testosterone (92% decrease in area under the curve), at a dose of 3 mg/kg. Quinolone 1 is a potent nonpeptidyl antagonist for the human GnRH receptor that is efficacious for the suppression of luteinizing hormone and testosterone in primates.


Subject(s)
Azetidines/chemical synthesis , Quinolones/chemical synthesis , Receptors, LHRH/antagonists & inhibitors , Animals , Azetidines/chemistry , Azetidines/pharmacokinetics , Azetidines/pharmacology , Binding, Competitive , CHO Cells , Cricetinae , Humans , In Vitro Techniques , Macaca mulatta , Pituitary Gland/metabolism , Quinolones/chemistry , Quinolones/pharmacokinetics , Quinolones/pharmacology , Radioligand Assay , Rats , Structure-Activity Relationship
6.
Bioorg Med Chem Lett ; 11(4): 509-13, 2001 Feb 26.
Article in English | MEDLINE | ID: mdl-11229759

ABSTRACT

A nonpeptidyl GnRH receptor antagonist (1), with a unique 2-arylindole core, was identified through the Merck in-house screening for binding affinity on the rat GnRH receptor. SAR studies directed toward the alkoxy-ethanolamine and 2-aryl groups resulted in a simpler lead structure with improved activity. This compound 50 exhibits a 60-fold improvement in binding activity over our initial lead 1.


Subject(s)
Indoles/pharmacology , Receptors, LHRH/antagonists & inhibitors , Animals , Rats , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 11(4): 515-7, 2001 Feb 26.
Article in English | MEDLINE | ID: mdl-11229760

ABSTRACT

The discovery of the potency-enhancing effect of 5-substitutions on the novel 2-arylindoles as nonpeptidyl GnRH receptor antagonists led to the identification of several analogues with high affinities on the GnRH receptor. The syntheses and SARs of these 5-substituted-2-arylindole analogues are reported.


Subject(s)
Indoles/pharmacology , Receptors, LHRH/antagonists & inhibitors , Animals , Rats , Structure-Activity Relationship
8.
Bioorg Med Chem Lett ; 11(3): 379-82, 2001 Feb 12.
Article in English | MEDLINE | ID: mdl-11212115

ABSTRACT

Pyridineethanolamine derivatives containing cyanoguanidine or nitroethylenediamine moieties were examined as human beta3 adrenergic receptor (AR) agonists. Notably, indoline derivatives 6a and 11 were potent beta3 AR agonists (beta3 EC50 = 13 and 19 nM, respectively), which showed good selectivity over binding to and minimal activation of the beta1 and beta2 ARs.


Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/chemical synthesis , Adenylyl Cyclases/drug effects , Adenylyl Cyclases/metabolism , Adrenergic beta-Agonists/chemistry , Adrenergic beta-Agonists/pharmacology , Animals , CHO Cells , Cell Membrane/chemistry , Combinatorial Chemistry Techniques , Cricetinae , Diamines/chemistry , Ethane/analogs & derivatives , Ethane/chemistry , Guanidines/chemistry , Humans , Inhibitory Concentration 50 , Nitroparaffins/chemistry , Radioligand Assay , Receptors, Adrenergic, beta/metabolism , Receptors, Adrenergic, beta-3/metabolism , Structure-Activity Relationship
11.
J Med Chem ; 43(25): 4919-22, 2000 Dec 14.
Article in English | MEDLINE | ID: mdl-11124001
12.
J Med Chem ; 43(21): 3832-6, 2000 Oct 19.
Article in English | MEDLINE | ID: mdl-11052788

ABSTRACT

As part of our investigation into the development of orally bioavailable beta(3) adrenergic receptor agonists, we have identified a series of pyridylethanolamine analogues possessing a substituted thiazole benzenesulfonamide pharmacophore that are potent human beta(3) agonists with excellent selectivity against other human beta receptor subtypes. Several of these compounds also exhibited an improved pharmacokinetic profile in dogs. For example, thiazole sulfonamide 2e (R = 4-F(3)C-C(6)H(4)) is a potent full beta(3) agonist (EC(50) = 3.6 nM, 94% activation) with >600-fold selectivity over the human beta(1) and beta(2) receptors, which also displays good oral bioavailability in several mammalian species, as well as an extended duration of action.


Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/chemical synthesis , Sulfonamides/chemical synthesis , Thiazoles/chemical synthesis , Administration, Oral , Adrenergic beta-Agonists/chemistry , Adrenergic beta-Agonists/pharmacokinetics , Adrenergic beta-Agonists/pharmacology , Animals , Biological Availability , CHO Cells , Cloning, Molecular , Cricetinae , Dogs , Glycerol/blood , Humans , Macaca mulatta , Male , Radioligand Assay , Rats , Receptors, Adrenergic, beta-1/metabolism , Receptors, Adrenergic, beta-2/metabolism , Receptors, Adrenergic, beta-3/metabolism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacokinetics , Thiazoles/pharmacology
13.
Bioorg Med Chem Lett ; 10(20): 2283-6, 2000 Oct 16.
Article in English | MEDLINE | ID: mdl-11055339

ABSTRACT

Tetrahydroisoquinoline derivatives containing a 4-(hexylureido)benzenesulfonamide were examined as human beta3 adrenergic receptor (AR) agonists. Notably, 4,4-biphenyl derivative 9 was a 6 nM full agonist of the beta3 AR. Naphthyloxy compound 18 (beta3 EC50 = 78 nM) did not activate the beta1 and beta2 ARs at 10 microM, and showed >1000-fold selectivity over binding to the beta1 and beta2 ARs.


Subject(s)
Adrenergic beta-3 Receptor Antagonists , Adrenergic beta-Agonists/chemical synthesis , Amides/chemical synthesis , Isoquinolines/chemical synthesis , Peptides/chemical synthesis , Adrenergic beta-Agonists/chemistry , Adrenergic beta-Agonists/pharmacology , Amides/chemistry , Drug Design , Humans , Isoquinolines/chemistry , Isoquinolines/pharmacology , Models, Molecular , Molecular Conformation , Peptides/chemistry , Receptors, Adrenergic, beta-1/metabolism , Receptors, Adrenergic, beta-2/metabolism , Receptors, Adrenergic, beta-3/metabolism , Recombinant Proteins/antagonists & inhibitors , Structure-Activity Relationship
14.
Bioorg Med Chem Lett ; 10(20): 2371-4, 2000 Oct 16.
Article in English | MEDLINE | ID: mdl-11055358

ABSTRACT

Medicinal chemistry efforts were initiated to identify the key constituents of the nodulisporic acid A (1) pharmacophore that are integral to its potent insecticidal activity. New semisynthetic derivatives delineated 1 into 'permissive' and 'nonpermissive' regions and led to the discovery of new nodulisporamides with significantly improved flea efficacy.


Subject(s)
Indoles/chemistry , Indoles/chemical synthesis , Insecticides/chemical synthesis , Animals , Drug Design , Indoles/pharmacology , Insecticides/chemistry , Insecticides/pharmacology , Molecular Structure , Siphonaptera , Structure-Activity Relationship
15.
Bioorg Med Chem Lett ; 10(17): 1971-3, 2000 Sep 04.
Article in English | MEDLINE | ID: mdl-10987429

ABSTRACT

A series of thiazole benzenesulfonamide-substituted 3-pyridylethanolamines was prepared and evaluated for their human beta3 adrenergic receptor agonist activity. Incorporation of aryl and heteroaryl substitution in the 4-position of the thiazole ring resulted in a number of highly potent and selective beta3 agonists. Results of preliminary in vivo evaluation of several of these compounds is described.


Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/chemical synthesis , Ethanolamines/chemical synthesis , Sulfonamides/chemical synthesis , Thiazoles/chemical synthesis , Adrenergic beta-Agonists/pharmacology , Animals , CHO Cells , Cricetinae , Humans , Structure-Activity Relationship , Benzenesulfonamides
16.
Bioorg Med Chem Lett ; 10(18): 2111-4, 2000 Sep 18.
Article in English | MEDLINE | ID: mdl-10999482

ABSTRACT

Compounds containing a 1,2,3-triazole-substituted benzenesulfonamide were prepared and found to be potent and selective human beta3-adrenergic receptor agonists. The most interesting compound, trifluoromethylbenzyl analogue 12e (beta3 EC50 = 3.1 nM with >1500-fold selectivity over binding to both beta1- and beta2 receptors), stimulates lipolysis in the rhesus monkey (ED50 = 0.36 mg/kg) and is 25% orally bioavailable in the dog.


Subject(s)
Adrenergic beta-3 Receptor Agonists , Administration, Oral , Animals , Biological Availability , CHO Cells , Cricetinae , Cyclic AMP/metabolism , Dogs , Dose-Response Relationship, Drug , Humans , Infusions, Parenteral , Isoproterenol/pharmacology , Lipolysis/drug effects , Macaca mulatta , Protein Binding , Receptors, Adrenergic, beta-3/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/metabolism , Sulfonamides/pharmacokinetics , Tachycardia/chemically induced , Triazoles/chemical synthesis , Triazoles/metabolism , Triazoles/pharmacokinetics , Benzenesulfonamides
17.
Bioorg Med Chem Lett ; 10(15): 1723-7, 2000 Aug 07.
Article in English | MEDLINE | ID: mdl-10937733

ABSTRACT

A series of 3-arylquinolones was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. A variety of substitution patterns of the 3-aryl substituent are described. The 3,4,5-trimethylphenyl substituent (23h) was found to be optimal.


Subject(s)
Gonadotropin-Releasing Hormone/antagonists & inhibitors , Quinolones/pharmacology , Quinolones/chemistry , Structure-Activity Relationship
18.
Bioorg Med Chem Lett ; 10(14): 1531-4, 2000 Jul 17.
Article in English | MEDLINE | ID: mdl-10915043

ABSTRACT

As a part of our investigation into the development of orally bioavailable beta3 adrenergic receptor agonists, we have identified a series of substituted oxazole derivatives that are potent beta3 agonists with excellent selectivity against other beta receptors. Several of these compounds showed excellent oral bioavailability in dogs. One example, cyclopentylethyloxazole 5f is a potent beta3 agonist (EC50 = 14 nM, 84% activation) with 340-fold and 160-fold selectivity over beta1 and beta2 receptors, respectively, and has 38% oral bioavailability in dogs.


Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/chemical synthesis , Adrenergic beta-Agonists/pharmacology , Oxazoles/chemical synthesis , Oxazoles/pharmacology , Sulfonamides/pharmacology , Adrenergic beta-Agonists/chemistry , Animals , Dogs , Humans , Indicators and Reagents , Kinetics , Molecular Structure , Oxazoles/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry
19.
Bioorg Med Chem Lett ; 10(13): 1427-9, 2000 Jul 03.
Article in English | MEDLINE | ID: mdl-10888324

ABSTRACT

5-n-Pentyl oxadiazole substituted benzenesulfonamide 8 is a potent and selective beta3 adrenergic receptor agonist (beta3 EC50 = 23 nM, beta1 IC50 = 3000 nM, beta2 IC50 = 3000 nM). The compound has high oral bioavailability in dogs (62%) and rats (36%) and is among the most orally bioavailable beta3 adrenergic receptor agonists reported to date.


Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/pharmacology , Adrenergic beta-Agonists/pharmacokinetics , Oxadiazoles/pharmacology , Oxadiazoles/pharmacokinetics , Administration, Oral , Adrenergic beta-Agonists/administration & dosage , Adrenergic beta-Agonists/chemistry , Animals , Biological Availability , CHO Cells , Cricetinae , Dogs , Drug Design , Humans , Molecular Structure , Oxadiazoles/administration & dosage , Oxadiazoles/chemistry , Rats , Structure-Activity Relationship
20.
Bioorg Med Chem Lett ; 10(13): 1431-4, 2000 Jul 03.
Article in English | MEDLINE | ID: mdl-10888325

ABSTRACT

Benzyl and phenoxymethylene substituted oxadiazoles are potent and orally bioavailable beta3 adrenergic receptor (AR) agonists. The 4-trifluormethoxy substituted 5-benzyl oxadiazole 5f has an EC50 of 8 nM in the beta3 AR agonist assay with 100-fold selectivity over beta1 and beta2 AR binding inhibition activity. Its oral bioavailability in dogs is 30 +/- 4%, with a half-life of 3.8 +/- 0.4 h. In the anesthetized rhesus, 5f evoked a dose-dependent glycerolemia (ED50Gly = 0.15 mg/kg). Under these conditions a heart rate increase of 15% was observed at a dose level of 10 mg/kg.


Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/pharmacology , Anti-Obesity Agents/pharmacology , Oxadiazoles/pharmacology , Sulfonamides/pharmacology , Adrenergic beta-Agonists/chemical synthesis , Adrenergic beta-Agonists/chemistry , Animals , Anti-Obesity Agents/chemical synthesis , Anti-Obesity Agents/chemistry , Biological Availability , CHO Cells , Cricetinae , Dogs , Drug Design , Glycerol/metabolism , Heart Rate/drug effects , Humans , Macaca mulatta , Oxadiazoles/chemical synthesis , Oxadiazoles/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry
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