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The Future of Peptide‐based Drugs
The suite of currently used drugs can be divided into two categories – traditional ‘small molecule’ drugs with typical molecular weights of <500 Da but with oral bioavailability, and much largerExpand
Discovery of a novel class of phosphodiesterase 10A inhibitors and identification of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the
TLDR
This PDE10A inhibitor is the first reported clinical entry for this mechanism in the treatment of schizophrenia and the discovery of 2-[4-(1-methyl-4-pyridin- 4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920). Expand
Discovery of (S)-6-(3-cyclopentyl-2-(4-(trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid as a hepatoselective glucokinase activator clinical candidate for treating type 2 diabetes
TLDR
19 is identified as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species, leading to its selection as a clinical development candidate for treating type 2 diabetes. Expand
Rational design and synthesis of an orally bioavailable peptide guided by NMR amide temperature coefficients
TLDR
It is shown that this approach can be used to explain the notable increase in oral bioavailability of a somatostatin analog, and is a rapid alternative to the elucidation of 3D structures of peptide drug leads, which has been a commonly used structure-guided approach in the past. Expand
Design and discovery of 6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (PF-04447943), a selective brain
TLDR
A novel PDE9A inhibitor identified using parallel synthetic chemistry and structure-based drug design (SBDD) and has advanced into clinical trials, confirming that it is a quality pharmacological tool for testing clinical hypotheses in disease states associated with impairment of cGMP signaling or cognition. Expand
Short Hydrophobic Peptides with Cyclic Constraints Are Potent Glucagon-like Peptide-1 Receptor (GLP-1R) Agonists.
Cyclic constraints are incorporated into an 11-residue analogue of the N-terminus of glucagon-like peptide-1 (GLP-1) to investigate effects of structure on agonist activity. Cyclization throughExpand
On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds
TLDR
A method is reported for the selective, on-resin N-methylation of cyclic peptides to generate compounds with drug-like membrane permeability and oral bioavailability, suggesting that conformation dictates the regiochemistry of the N- methylation reaction. Expand
Discovery of a series of 6,7-dimethoxy-4-pyrrolidylquinazoline PDE10A inhibitors.
TLDR
A papaverine based pharmacophore model for PDE10A inhibition was generated via SBDD and used to design a library of 4-amino-6,7-dimethoxyquinazolines, which became the focal point for additional modeling, X-ray, and synthetic efforts toward increasing PDE 10A inhibitory potency and selectivity versus PDE3A/B. Expand
Optimizing PK properties of cyclic peptides: the effect of side chain substitutions on permeability and clearance().
TLDR
A series of cyclic peptides were designed and prepared to investigate the physicochemical properties that affect oral bioavailabilty of this chemotype in rats and the usefulness of this data in predicting the subsequent oral bioavailability observed in the rat is discussed. Expand
Designing glucokinase activators with reduced hypoglycemia risk: discovery of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benzofuran-4-yloxy)pyrimidine-2-carboxamide as a clinical
TLDR
This work has investigated a series of substituted 2-methylbenzofurans as “partial activators” of the glucokinase enzyme leading to the identification of N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)-carbamoyl)benz ofuran-4-yloxy)pyrimidine- 2-carboxamide as an early development candidate. Expand
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