A recent publication from AstraZeneca provides a really interesting overview of the approach that they took to optimise the solubility of a series of GPR119 agonists. The initial lead compound 2 was only poorly soluble but, by obtaining small molecule x-ray structures of this and subsequent compounds, the AZ team were able to identify H-bonding networks within the crystal lattice and to target molecular features with the potential to disrupt these and other intermolecular interactions, thus lowering the melting point and increasing aqueous solubility. The paper describes this process in some detail and also highlights other key strategies that were used to progress from compound 2 through to 42, a clinical candidate for treating type II diabetes. The paper also serves to illustrate and build upon the concepts described in the review that we blogged previously.
- Review: Bioisosteres in Drug Design
- Optimization of plasma protein binding (again...)
- Improved PK profile through fluorine and deuterium incorporation
- Discovery of PF-04691502 (PI3K/mTOR dual inhibitor)
- The Discovery of RG1678 (Gly-T1 inhibitor)
- Discovery of MK-1220 (Hepatitis C NS3/4A protease inhibitor)
- Abbott adverse events allosteric allosteric inhibitor amine basicity Analgesic animal PK anti-viral AstraZeneca Aurora beta-secretase bioactivation BIRB-796 Boehringer Ingelheim cancer cardiotoxicity cellular potency CGRP chloro CNS penetration computational method crystal packing CYP450 Deuterium Doramapimod FAAH Fatty acid amide hydrolase fluorine free drug functional antagonist Gly-T1 gpcr hepatotoxicity hERG immunosuppressant isostere kinase kinetic isotope effect Lexicon Pharmaceuticals LipE Merck metabolism mTOR nitrile Novartis osteoarthritis P-gp p38 Pain PF-04457845 PF-3845 Pfizer Phase I Phase II Phase III POC PPB protein binding PSA reactive metabolite review RG1678 rheumatoid arthritis Roche S1P1 S1PL Schizophrenia solubility Structural alert Structure Based Design switch pocket synthesis toxicity Transporters X-ray data