Carl P. Ciosek

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

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)

BMS-196085: A potent and selective full agonist of the human β3 adrenergic receptor

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.

Aromatic isosteres as conformational probes for an isoprenyl subunit: application to inhibitors of squalene synthase

Abstract A series of aromatic isosteres of the farnesyl chain of potent squalene synthase inhibitor 1 were prepared and evaluated. The results are consistent with the local conformation indicated in structure 2 .

3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors: oxime ether analogs of pravastatin

Pravastatin, a potent anti-hypercholesteremic drug, has been developed by Bristol-Myers Squibb for treatment of hypercholesterolemia and other related diseases. Several structurally related compounds (SQ 31,554, SQ 31,879, SQ 31,947, SQ 32,391, SQ 32,770, SQ 32,390 and SQ 32,469) modified at the 3-position of the hexahydronaphthalene ring system of pravastatin were prepared in the course of developing the basic reagents for a radioimmunoassay of the parent drug. The biological activity of these analogs was comparable to pravastatin itself. Indeed, one member of this series was found to be several times more potent than pravastatin.