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Biomedical subjects

M H Fisher

Publications and source records attributed to M H Fisher.

At least 37 records · Page 2Linked to original sources
PubMed2000

Potent, selective 3-pyridylethanolamine beta3 adrenergic receptor agonists possessing a thiazole benzenesulfonamide pharmacophore.

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.

Adrenergic beta-3 Receptor Agonists↗
PubMed2000

Substituted oxazole benzenesulfonamides as potent human beta3 adrenergic receptor agonists.

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.

Adrenergic beta-3 Receptor Agonists↗
PubMed2000

Discovery of an orally bioavailable alkyl oxadiazole beta3 adrenergic receptor agonist.

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.

Administration, Oral↗
PubMed2000

Synthesis and SAR of benzyl and phenoxymethylene oxadiazole benzenesulfonamides as selective beta3 adrenergic receptor agonist antiobesity agents.

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.

Adrenergic beta-3 Receptor Agonists↗
PubMed2000

Potent antagonists of gonadotropin releasing hormone receptors derived from quinolone-6-carboxamides.

SAR studies which focused upon the C-6 position of a recently described series of quinolone gonadotropin releasing hormone antagonists are reported. Synthetic access to diverse quinolone-6-carboxamides was achieved via the palladium-catalyzed amino-carbonylation reactions of iodide 4 with various amines. Amides related to 9y were especially potent, functional antagonists of rat and human GnRH receptors.

Amides↗
PubMed1999

Identification and initial structure-activity relationships of a novel non-peptide quinolone GnRH receptor antagonist.

Screening of the Merck sample collection for non-peptide compounds with binding affinity for the rat GnRH receptor led to the identification of the substituted quinolone (1) as a lead compound in the search for a non-peptide GnRH receptor antagonist. Substantial improvements in potency (approximately 300 fold) were achieved by addition of an alkyl amine at the 4-position, a 3,5-dimethylphenyl group at the 3-position and 6-nitro-7-chloro-substitution of the 1 H-quinolone core.

Animals↗
PubMed1999

Investigation of the 4-O-alkylamine substituent of non-peptide quinolone GnRH receptor antagonists.

Synthesis and in vitro activity of the enantiomers of quinolone GnRH antagonist (+/-)-1 are reported. Chiral amino alcohols were prepared from the appropriate cyclic D- or L-amino acids by the Amdt-Eistert homologation followed by reduction of the resulting esters. Incorporation of these pharmacophores was achieved via a novel Mitsunobu alkylation of 4-hydroxyquinolones. The key amine pharmacophore for binding to the rat GnRH receptor was most active in the S-configuration. Ring size was not important for potency with 4, 5, 6, and 7-membered ring amines exhibiting similar potency.

Animals↗
PubMed1999

Potent, elective human beta3 adrenergic receptor agonists containing a substituted indoline-5-sulfonamide pharmacophore.

A series of compounds possessing an N-substituted indoline-5-sulfonamide pharmacophore was prepared and evaluated for their human beta3 adrenergic receptor agonist activity. The SAR of a wide range of urea and heterocyclic substituents is discussed. 4-Octyl thiazole compound 8c was the most potent and selective compound in the series, with 2800-fold selectivity over beta1 binding and 1400-fold selectivity over beta2 binding.

Adrenergic Agonists↗
PubMed1999

L-770,644: a potent and selective human beta3 adrenergic receptor agonist with improved oral bioavailability.

L-770,644 (9c) is a potent and selective agonist of the human beta3 adrenergic receptor (EC50 = 13 nM). It shows good oral bioavailability in both dogs and rats (%F = 27), and is a full agonist for glycerolemia in the rhesus monkey (ED50 = 0.21 mg/kg). Based on its desirable in vitro and in vivo properties, L-770,644 was chosen for further preclinical evaluation.

Administration, Oral↗
PubMed1999

Human beta3 adrenergic receptor agonists containing cyclic ureidobenzenesulfonamides.

Human beta3 adrenergic receptor agonists containing 5-membered ring ureas were shown to be potent partial agonists with excellent selectivity over beta1 and beta2 binding. L-760,087 (4a) and L-764,646 (5a) (beta3 EC50 = 18 and 14 nM, respectively) stimulate lipolysis in rhesus monkeys (ED50 = 0.2 and 0.1 mg/kg, respectively) with minimal effects on heart rate. Oral absorption in dogs is improved over other urea analogs.

Administration, Oral↗
PubMed1998

Synthesis of gem-difluoro-avermectin derivatives: potent anthelmintic and anticonvulsant agents.

A series of gem-difluoro-avermectin derivatives was synthesized from the corresponding ketones at positions 4", 4', 13, and 23 using diethylaminosulfur trifluoride (DAST). These fluorinated avermectins exhibit potent antiparasitic activity in a new Haemonchus contortus larval assay and are equipotent to ivermectin. In addition, 23-gem-difluoro-ivermectin displays useful anticonvulsant activity in mouse models.

Animals↗
PubMed1998

3-Pyridyloxypropanolamine agonists of the beta 3 adrenergic receptor with improved pharmacokinetic properties.

Pyridyloxypropanolamines L-749,372 (8, beta 3 EC50 = 3.6 nM) and L-750,355 (29, beta 3 EC50 = 13 nM) are selective partial agonists of the human receptor, with 33% and 49% activation, respectively. Both stimulate lipolysis in rhesus monkeys (ED50 = 2 and 0.8 mg/kg, respectively), with minimal effects on heart rate. Oral bioavailability in dogs, 41% for L-749,372 and 47% for L-750,355, is improved relative to phenol analogs.

Adrenergic beta-Agonists↗
PubMed1998

A selective human beta3 adrenergic receptor agonist increases metabolic rate in rhesus monkeys.

Activation of beta3 adrenergic receptors on the surface of adipocytes leads to increases in intracellular cAMP and stimulation of lipolysis. In brown adipose tissue, this serves to up-regulate and activate the mitochondrial uncoupling protein 1, which mediates a proton conductance pathway that uncouples oxidative phosphorylation, leading to a net increase in energy expenditure. While chronic treatment with beta3 agonists in nonprimate species leads to uncoupling protein 1 up-regulation and weight loss, the relevance of this mechanism to energy metabolism in primates, which have much lower levels of brown adipose tissue, has been questioned. With the discovery of L-755,507, a potent and selective partial agonist for both human and rhesus beta3 receptors, we now demonstrate that acute exposure of rhesus monkeys to a beta3 agonist elicits lipolysis and metabolic rate elevation, and that chronic exposure increases uncoupling protein 1 expression in rhesus brown adipose tissue. These data suggest a role for beta3 agonists in the treatment of human obesity.

Adipose Tissue, Brown↗
PubMed1998

A potent, orally bioavailable benzazepinone growth hormone secretagogue.

The identification of L-739,943 (8b), a potent, orally bioavailable benzolactam growth hormone secretagogue, is obtained from zwitterionic L-692,429 through modification of its amino acid side chain and replacement of the acidic 2'-tetrazole with the neutral and potency enhancing 2'-(N-methylaminocarbonylamino)methyl substituent. L-739,943 is orally active for the release of growth hormone in beagle dogs at doses as low as 0.5 mg/kg. Oral bioavailability in dogs of 8b is 24% at a dose of 2 mg/kg with a mean drug Cmax of 145 +/- 46 ng/mL. L-739,943 represents a significant breakthrough in terms of both potency and oral bioavailability as compared to the prototype benzolactam L-692,429.

Administration, Oral↗
PubMed1998

Potent, selective benzenesulfonamide agonists of the human beta 3 adrenergic receptor.

A cloned human beta 3 adrenergic receptor assay was used to identify phenoxypropanolamine agonist 1. SAR studies led to the identification of benzenesulfonamide derivative 20, a 6.3 nM beta 3 agonist which shows 30-fold selectivity for beta 3 agonist activity over beta 1 and beta 2 receptor binding. Further refinement of this lead provided 4-bromo derivative 39, a subnanomolar agonist with 660-fold and 230-fold selectivity over beta 1 and beta 2, respectively.

Adrenergic beta-Agonists↗