ABSTRACT
Utilization of N-substituted-4-hydroxy-3-methylsulfonanilidoethanolamines 1 as selective beta(3) agonists is complicated by their propensity to undergo metabolic oxidative N-dealkylation, generating 0.01-2% of a very potent alpha(1) adrenergic agonist 2. A summary of the SAR for this hepatic microsomal conversion precedes presentation of strategies to maintain the advantages of chemotype 1 while mitigating the consequences of N-dealkylation. This effort led to the identification of 4-hydroxy-3-methylsulfonanilidopropanolamines 15 for which the SAR for the unique stereochemical requirements for binding to the beta adrenergic receptors culminated in the identification of the potent, selective beta(3) agonist 15f.
Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/pharmacology , Propanolamines/pharmacology , Adrenergic beta-Agonists/chemistry , Alkylation , Oxidation-Reduction , Propanolamines/chemistry , Structure-Activity RelationshipABSTRACT
A series of N-(4-hydroxy-3-methylsulfonanilidoethanol)arylglycinamides were prepared and evaluated for their human beta3 adrenergic receptor agonist activity. SAR studies led to the identification of BMS-201620 (39), a potent beta3 full agonist (Ki = 93 nM, 93% activation). Based on its favorable safety profile, BMS-201620 was chosen for clinical evaluation.
Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/pharmacology , Glycine/analogs & derivatives , Glycine/pharmacology , Adrenergic beta-Agonists/chemical synthesis , Animals , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Glycine/chemical synthesis , Glycine/chemistry , Haplorhini , Humans , Methylation , Receptors, Adrenergic, beta-3/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Screening of the BMS collection identified 4-hydroxy-3-methylsulfonanilidoethanolamines as full beta 3 agonists. Substitution of the ethanolamine nitrogen with a benzyl group bearing a para hydrogen bond acceptor promoted beta(3) selectivity. SAR elucidation established that highly selective beta(3) agonists were generated upon substitution of C(alpha) with either benzyl to form (R)-1,2-diarylethylamines or with aryl to generate 1,1-diarylmethylamines. This latter subset yielded a clinical candidate, BMS-194449 (35).(1)
Subject(s)
Adrenergic beta-3 Receptor Agonists , Adrenergic beta-Agonists/chemistry , Adrenergic beta-Agonists/pharmacology , Anilides/chemistry , Anilides/pharmacology , Ethanolamine/chemistry , Ethanolamine/pharmacology , Administration, Oral , Animals , Biological Availability , Chlorocebus aethiops , Drug Evaluation, Preclinical , Ethanolamines , Humans , Rats , Structure-Activity RelationshipABSTRACT
A series of 4-hydroxy-3-methylsulfonanilido-1,2-diarylethylamines were prepared and evaluated for their human beta(3) adrenergic receptor agonist activity. SAR studies led to the identification of BMS-196085 (25), a potent beta(3) full agonist (K(i)=21 nM, 95% activation) with partial agonist (45%) activity at the beta(1) receptor. Based on its desirable in vitro and in vivo properties, BMS-196085 was chosen for clinical evaluation.
Subject(s)
Adrenergic Agonists/chemistry , Adrenergic Agonists/pharmacology , Adrenergic beta-3 Receptor Agonists , Anilides/chemistry , Anilides/pharmacology , Administration, Oral , Adrenergic beta-1 Receptor Agonists , Animals , Blood Glucose/metabolism , Chlorocebus aethiops , Drug Evaluation, Preclinical , Fatty Acids/blood , Humans , Mice , Mice, Obese , Receptors, Adrenergic, beta-1/metabolism , Receptors, Adrenergic, beta-3/metabolism , Structure-Activity RelationshipSubject(s)
Farnesyl-Diphosphate Farnesyltransferase/antagonists & inhibitors , Hypolipidemic Agents/pharmacology , Sulfonic Acids/pharmacology , Animals , Cholesterol/blood , Cricetinae , Hypolipidemic Agents/chemistry , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Molecular Conformation , Rats , Sulfonic Acids/chemistryABSTRACT
A series of 2,3,4,(5),6-substituted pyridines containing a hydroxyphosphinyl functionally have been prepared and were evaluated for their ability to inhibit the enzyme HMG-CoA reductase. Systematic substitution of both R1-R4 and X-Y led to compounds of type 3-6 with in vitro potency greater than that of mevinolin (Na salt).
