Development of a Novel Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist (CH5447240), a Potent and Orally Available Small Molecule for Treatment of Hypoparathyroidism

During the course of derivatization of HTS hit <b>4a</b>, we have identified a novel small-molecule hPTHR1 agonist, 1-(3,5-dimethyl-4-(2-((2-((1<i>R</i>,4<i>R</i>)-4-methylcyclohexyl)-4-oxo-1,3,8-triazaspiro­[4.5]­dec-1-en-8-yl)­sulfonyl)­ethyl)­phenyl)-1-methylurea (CH5447240, <b>14l</b>). Compound <b>14l</b> exhibited a potent in vitro hPTHR1 agonist effect with EC₂₀ of 3.0 μM and EC₅₀ of 12 μM and showed excellent physicochemical properties, such as high solubility in fasted state simulated intestinal fluid and good metabolic stability in human liver microsomes. Importantly, <b>14l</b> showed 55% oral bioavailability and a significantly elevated serum calcium level in hypocalcemic model rats

Development of a Novel Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist (CH5447240), a Potent and Orally Available Small Molecule for Treatment of Hypoparathyroidism

During the course of derivatization of HTS hit <b>4a</b>, we have identified a novel small-molecule hPTHR1 agonist, 1-(3,5-dimethyl-4-(2-((2-((1<i>R</i>,4<i>R</i>)-4-methylcyclohexyl)-4-oxo-1,3,8-triazaspiro­[4.5]­dec-1-en-8-yl)­sulfonyl)­ethyl)­phenyl)-1-methylurea (CH5447240, <b>14l</b>). Compound <b>14l</b> exhibited a potent in vitro hPTHR1 agonist effect with EC₂₀ of 3.0 μM and EC₅₀ of 12 μM and showed excellent physicochemical properties, such as high solubility in fasted state simulated intestinal fluid and good metabolic stability in human liver microsomes. Importantly, <b>14l</b> showed 55% oral bioavailability and a significantly elevated serum calcium level in hypocalcemic model rats

Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor

Cyclic peptides as a therapeutic modality are attracting a lot of attention due to their potential for oral absorption and accessibility to intracellular tough targets. Here, starting with a drug-like hit discovered using an mRNA display library, we describe a chemical optimization that led to the orally available clinical compound known as LUNA18, an 11-mer cyclic peptide inhibitor for the intracellular tough target RAS. The key findings are as follows: (i) two peptide side chains were identified that each increase RAS affinity over 10-fold; (ii) physico-chemical properties (PCP) including Clog P can be adjusted by side-chain modification to increase membrane permeability; (iii) restriction of cyclic peptide conformation works effectively to adjust PCP and improve bio-activity; (iv) cellular efficacy was observed in peptides with a permeability of around 0.4 × 10–6 cm/s or more in a Caco-2 permeability assay; and (v) while keeping the cyclic peptide’s main-chain conformation, we found one example where the RAS protein structure was changed dramatically through induced-fit to our peptide side chain. This study demonstrates how the chemical optimization of bio-active peptides can be achieved without scaffold hopping, much like the processes for small molecule drug discovery that are guided by Lipinski’s rule of five. Our approach provides a versatile new strategy for generating peptide drugs starting from drug-like hits