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

Abstract

During the course of derivatization of HTS hit 4a, we have identified a novel small-molecule hPTHR1 agonist, 1-(3,5-dimethyl-4-(2-((2-((1 R,4 R)-4-methylcyclohexyl)-4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-8-yl)sulfonyl)ethyl)phenyl)-1-methylurea (CH5447240, 14l). Compound 14l exhibited a potent in vitro hPTHR1 agonist effect with EC of 3.0 μM and EC 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, 14l showed 55% oral bioavailability and a significantly elevated serum calcium level in hypocalcemic model rats.

Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist

“…As a metabolically unstable and stable moiety, the methylcyclohexyl group of 1 was replaced with the ethylcyclohexyl group 9a and 4-trifluoromethoxyphenyl group 9b, respectively, because in a previous SAR study on spiroimidazole derivatives only the 2-position of imidazolone accepted hydrophobic groups. 12 The agonistic activities of 9a and 9b were comparable to that of 1, reconfirming the presence of the hydrophobic pharmacophore at the 2-position of the imidazolone ring. Importantly, as shown by the GSH assay, 9a was not metabolized to GSH-adduct, and the in vitro metabolic clearance of 9a was considerably higher than that of 1, suggesting that the metabolism pathway was changed by the insertion of metabolically unstable moiety.…”

“…As a metabolically unstable and stable moiety, the methylcyclohexyl group of 1 was replaced with the ethylcyclohexyl group 9a and 4-trifluoromethoxyphenyl group 9b , respectively, because in a previous SAR study on spiroimidazole derivatives only the 2-position of imidazolone accepted hydrophobic groups . The agonistic activities of 9a and 9b were comparable to that of 1 , reconfirming the presence of the hydrophobic pharmacophore at the 2-position of the imidazolone ring.…”

“…Hydrogenation of 7b and acylation of 8b gave 9b . The Heck reaction of vinylsulfonamides 6b , c , with aryl bromide 12 gave trans -olefins 10b , c , followed by hydrogenation-afforded imide-bonded hydantoin derivatives 9c , d .…”

“…Recently, we reported the identification and hit-to-lead modification of the orally active small molecule PTHR1 agonist 1 (CH5447240) (Figure 1). 12 However, glutathione (GSH)-adduct, derived from a reactive metabolite of 1, was detected in a human liver microsome (hLM) study. Reactive metabolites are responsible for unexpected toxicities because of their reaction with proteins and DNAs and thus further modifications are required for the selection of clinical candidate.…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–4

“…The paper herein details the discovery of a potent, orally bioavailable small molecule PTHR1 agonist, claimed to be the precursor to the clinical candidate PCO371 being evaluated as a treatment for hypoparathyroidism. The translation of 1-34mer peptidic agonistic activity into a small molecule is a significant achievement [6] and if studies are directed towards osteoporosis, the cost of goods should be significantly less than for teriparatide.…”