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1. Beta 3 agonists. Part 1: evolution from inception to BMS-194449.

Author

Washburn WN, Sher PM, Poss KM, Girotra RN, McCann PJ, Gavai AV, Mikkilineni AB, Mathur A, Cheng P, Dejneka TC, Sun CQ, Wang TC, Harper TW, Russell AD, Slusarchyk DA, Skwish S, Allen GT, Hillyer DE, Frohlich BH, Abboa-Offei BE, Cap M, Waldron TL, George RJ, Tesfamariam B, Ciosek CP Jr, Ryono D, Young DA, Dickinson KE, Seymour AA, Arbeeny CM, and Gregg RE

Subjects
Administration, Oral, Animals, Biological Availability, Chlorocebus aethiops, Drug Evaluation, Preclinical, Ethanolamines, Humans, Rats, Structure-Activity Relationship, Adrenergic beta-3 Receptor Agonists, Adrenergic beta-Agonists chemistry, Adrenergic beta-Agonists pharmacology, Anilides chemistry, Anilides pharmacology, Ethanolamine chemistry, Ethanolamine pharmacology
Abstract

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)

Published
2001
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2. BMS-196085: a potent and selective full agonist of the human beta(3) adrenergic receptor.

Author

Gavai AV, Sher PM, Mikkilineni AB, Poss KM, McCann PJ, Girotra RN, Fisher LG, Wu G, Bednarz MS, Mathur A, Wang TC, Sun CQ, Slusarchyk DA, Skwish S, Allen GT, Hillyer DE, Frohlich BH, Abboa-Offei BE, Cap M, Waldron TL, George RJ, Tesfamariam B, Harper TW, Ciosek CP Jr, Young DA, Dickinson KE, Seymour AA, Arbeeny CM, and Washburn WN

Subjects
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 Relationship, Adrenergic Agonists chemistry, Adrenergic Agonists pharmacology, Adrenergic beta-3 Receptor Agonists, Anilides chemistry, Anilides pharmacology
Abstract

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.

Published
2001
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