Antagonists of the Calcium Receptor I. Amino Alcohol-Based Parathyroid Hormone Secretagogues

Abstract

Functional screening of the former SmithKline Beecham compound collection against the human calcium receptor (CaR) resulted in the identification of the amino alcohol-based hit 2 (IC(50) = 11 microM). Structure-activity studies of 2 focused on the optimization of the right- and left-hand side aromatic moieties as well as the amino alcohol linker region. Critical to the optimization of this antagonist template was the discovery that the chirality of the C-2 secondary alcohol played a key role in enhancing both CaR potency as well as selectivity over the beta-adrenergic receptor subtypes. These SAR studies ultimately led to the identification of 38 (NPS 2143; SB-262470A), a potent and orally active CaR antagonist. Pharmacokinetic characterization of 38 in the rat revealed that this molecule had a large volume of distribution (11 L/kg), which resulted in a prolonged systemic exposure, protracted increases in the plasma levels of PTH, and an overall lack of net bone formation effect in a rodent model of osteoporosis.

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

“…Whereas the effects of NPS2143 on PTH levels are undesirably long-lasting, compound V in Table 13 stimulates PTH secretion in vivo in a more transient fashion (Arey et al, 2005). The reason for the sustained action of NPS2143 is most likely its large volume of distribution (11 l/kg in the rat), resulting in prolonged drug exposure and elevation of PTH levels (Marquis et al, 2009a). The addition of a carboxylic acid functionality to the amino alcohol NPS2143-template resulted in the zwitterionic compound IX (Table 13, r ϭ H) with an approximately 10-fold lower volume of distribution and a shorter half-life (Marquis et al, 2009b).…”

Calcilytics: Antagonists of the Calcium-Sensing Receptor for the Treatment of Osteoporosis

“…It is a compound containing an aminoalcohol core unit. SB-222338 was neither very potent (IC 50 = 11 µM) nor specific, most notably exhibiting potent binding to b-adrenoreceptor family members [33]. Extensive structure-activity relationship studies to optimize antagonistic potency and reduce off-target interactions led to the identification of NPS 2143 with an IC 50 of 43 nM, an improvement of more than a factor of 100 compared with the lead [34,35].…”

“…Consequently, higher bone turnover was observed rather than the desired anabolic net increase in bone mass. Only by blocking the increased bone resorption with the antiresorptive agent 17b-estradiol could a gain in BMD be achieved [33,34]. Further work focused on the improvement of the pharmacokinetic (PK) properties of NPS 2143 [36].…”

Synthesis of the calcilytic ligand NPS 2143

“…Similar to a previously reported synthesis of ( R )- 3 [13], we decided to activate epoxide 5 as the m -nosyl derivative that has been shown to minimise racemisation during epoxide ring opening [15]. …”

“…Moreover, we were surprised to discover the lack of assessment of optical purity for ( R )- 3. Considering that the R -enantiomer of ( R )- 3 and related aminoalcohols display both significantly higher potency and target selectivity than their S -enantiomers, we believe that this is a critical shortcoming in the previously reported syntheses [13–14]. …”