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Discovery of novel somatostatin receptor subtype 5 (SSTR5) antagonists: Pharmacological studies and design to improve pharmacokinetic profiles and human Ether-a-go-go-related gene (hERG) inhibition
- Source :
- Bioorganic & Medicinal Chemistry. 25:4153-4162
- Publication Year :
- 2017
- Publisher :
- Elsevier BV, 2017.
-
Abstract
- Somatostatin (SST) is a peptide hormone comprising 14 or 28 amino acids that inhibits endocrine and exocrine secretion via five distinct G-protein-coupled receptors (SSTR1-5). SSTR5 has an important role in inhibiting the secretion of pancreatic and gastrointestinal hormones (e.g., insulin, GLP-1, PYY) through the binding of SSTs; hence, SSTR5 antagonists are expected to be novel anti-diabetic drugs. In the course of our lead generation program of SSTR5 antagonists, we have discovered a novel spiroazetidine derivative 3a. However, pharmacological evaluation of 3a revealed that it had to be administered at a high dose (100mg/kg) to show a persistent glucose-lowering effect in an oral glucose tolerance test (OGTT). We therefore initiated an optimization study based on 3a aimed at improving the antagonistic activity and mean residence time (MRT), resulting in the identification of 2-cyclopropyl-5-methoxybiphenyl derivative 3k. However, 3k did not show a sufficient persistent glucose-lowering effect in an OGTT; moreover, hERG inhibition was observed. Hence, further optimization study of the biphenyl moiety of compound 3k, focused on improving the pharmacokinetic (PK) profile and hERG inhibition, was conducted. Consequently, the introduction of a chlorine atom at the 6-position on the biphenyl moiety addressed a putative metabolic soft spot and increased the dihedral angle of the biphenyl moiety, leading to the discovery of 3p with an improved PK profile and hERG inhibition. Furthermore, 3p successfully exhibited a persistent glucose-lowering effect in an OGTT at a dose of 3mg/kg.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
Clinical Biochemistry
hERG
Pharmaceutical Science
Peptide hormone
Pharmacology
Biochemistry
03 medical and health sciences
0302 clinical medicine
Pharmacokinetics
Internal medicine
Drug Discovery
medicine
Humans
Hypoglycemic Agents
Receptors, Somatostatin
Receptor
Molecular Biology
Glucose tolerance test
biology
medicine.diagnostic_test
Chemistry
Somatostatin receptor
Organic Chemistry
Glucose Tolerance Test
Ether-A-Go-Go Potassium Channels
030104 developmental biology
Endocrinology
Somatostatin
Gene Expression Regulation
Drug Design
030220 oncology & carcinogenesis
biology.protein
Molecular Medicine
Hormone
Subjects
Details
- ISSN :
- 09680896
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....e7e142ba64317c5da625db4c39b32b21