Biomedical subjects
Publications and source records attributed to M Cap.
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.
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)
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.
Patients with abetalipoproteinemia, a disease caused by defects in the microsomal triglyceride transfer protein (MTP), do not produce apolipoprotein B-containing lipoproteins. It was hypothesized that small molecule inhibitors of MTP would prevent the assembly and secretion of these atherogenic lipoproteins. To test this hypothesis, two compounds identified in a high-throughput screen for MTP inhibitors were used to direct the synthesis of a highly potent MTP inhibitor. This molecule (compound 9) inhibited the production of lipoprotein particles in rodent models and normalized plasma lipoprotein levels in Watanabe-heritable hyperlipidemic (WHHL) rabbits, which are a model for human homozygous familial hypercholesterolemia. These results suggest that compound 9, or derivatives thereof, has potential applications for the therapeutic lowering of atherogenic lipoprotein levels in humans.
A model of early atherosclerosis in hamsters with moderate hypercholesterolemia (217 to 271 mg/dL) was established that was highly responsive to exogenous antioxidants. A key feature of this model was elevation of vascular oxidative stress by use of a diet deficient in nutritional antioxidants and supplemented with corn oil (10%) and cholesterol (0.2%, 0.4%, or 0.8%). After 10 weeks on the 0.4% cholesterol diet, mean plasma alpha-tocopherol levels declined from 5.68 +/- 0.30 to 1.27 +/- 0.15 micrograms/mL, while monocyte-macrophage foam cell lesions in the aortic arch, as assayed by video microscopy/image analysis of oil red O-stained histological specimens, increased from undetectable at week 0 to 60,900 +/- 5400 microns 2 per specimen at week 10 (mean +/- SEM, n = 36). alpha-Tocopherol or probucol administered for 10 weeks markedly suppressed LDL oxidation ex vivo and profoundly inhibited aortic foam cell formation. However, the effects of antioxidants on aortic lesions were attenuated at higher plasma cholesterol levels, although LDL oxidation ex vivo was effectively inhibited. With a plasma cholesterol level at approximately 250 mg/dL, the maximum effect of alpha-tocopherol on lesion size reached approximately 36% of control value, and the dose for half-maximal effect was approximately 10 mg.kg-1.d-1, which resulted in a plasma alpha-tocopherol value of approximately 20 micrograms/mL. Under these conditions a linear, inverse correlation of aortic lesion size and plasma alpha-tocopherol concentration was observed (n = 68, r = -0.581, P < .001). The data demonstrate that LDL oxidation is a significant component of early atherogenesis in this model but suggest that hyperlipidemia can outweigh the therapeutic effectiveness of antioxidants. The high sensitivity of aortic lesion initiation to alpha-tocopherol in hamsters maintained on moderately hypercholesterolemic diets depleted of endogenous antioxidants demonstrates that vascular oxidative stress can be isolated from other causative factors in an in vivo model of atherosclerosis.
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