Metabolic screening expansion

The lead 4 for delavirdine (6) was discovered in a screened set of 1,500 computationally diverse representatives of the Upjohn compound collection. There is only one literature ref." to the delavirdine lead structural type, exemplified by compound 7, prior to the disclosure of RT inhibitory activity for this class. Rapid SAR expansion of the lead was enabled by /V-benzyl connectivity and many alkylated and acylated variations of the upper portion of the piperazine scaffold were explored. Ultimately the acylindole, initially bearing a 5-methoxy substituent as in the first clinical candidate atevirdine (5), emerged as preferred. This was found to be metabolically labile and was subsequently replaced with the methylsulfonamide group. Early work also identified the /V-ethyl substituent of the lead as a potential metabolic liability and, although this pattern was retained in the first clinical candidate, it was replaced by the A-isopro-pyl substituent in the approved drug, delavirdine (6). 

The same lead structure, sulfisoxazole (11), was also identified by Bristol Meyers Squibb, via the screening hit sulfathiazole (14). In this instance modification of the aniline led, via a naphthalene ring, to the substituted biphenyl 15 " however, preclinical PK studies indicated that the attached isobutyl group was subject to extensive hydroxy-lation. Replacement of this group with an isoxazole ring imparted metabolic stability, and expansion of the SAR at the tolerant 2 -position provided the clinical candidate edo-nentan (16). ... 

Patients with CKD are at increased risk of cardiovascular disease, independent of the etiology of their kidney disease. While a clearly unique pathogenesis of cardiovascular disease specific to CKD has not been identified, it is known that manifestations of kidney disease are contributory. Risk factors for cardiovascular disease in this population include hemodynamic and metabolic abnormalities, as well as hypertension, dyslipidemia, elevated homocysteine levels, anemia, hyperparathyroidism, malnutrition, and oxidative stress. Hypertension induced by volume expansion and increased systemic vascular resistance increases myocardial work and contributes to development of left ventricular hypertrophy (LVH). Hyperlipidemia may enhance atherogenesis, while some uremic toxins can decrease myocardial contractflity. In addition, uremic toxins can induce pericarditis, a potentially fatal complication. Currently, measures to screen this high-risk population for cardiovascular risk factors are not routine. ... 

The success of newborn screening for phenylketonuria (PKU) led to the expansion of newborn screening for other disorders, including many inborn errors of metabolism, thus preventing significant morbidity and mortality. 

With the expansion of newborn screening in the last decade, it is common that many providers not familiar with inborn errors of metabolism are under the assumption that a normal newborn screen excludes inborn errors of metabolism in the differential diagnosis. While newborn screening is a very helpful tool, it is only one piece of the puzzle of a diagnostic work-up. If clinical concerns arise for an inborn error of metabolism, one should not rely on a newborn screening, but rather pursue further diagnostic work-up to investigate the possibility of a metabolic disorder (Box 2.5). 

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