Pharmacokinetics and Absorption of the Anticancer Agents Dasatinib and GDC-0941 under Various Gastric Conditions in Dogs – Reversing the Effect of Elevated Gastric pH with Betaine HCl

Changes in gastric pH can impact the dissolution and absorption of compounds presenting pH-dependent solubility. We assessed, in dogs, the effects of gastric pH-modifying agents on the oral absorption of two weakly basic anticancer drugs, dasatinib and GDC-0941. We also tested whether drug-induced hypochlorhydria could be temporarily mitigated using betaine HCl. Pretreatments with pentagastrin, famotidine, betaine HCl, or combinations of famotidine and betaine HCl were administered orally to dogs prior to drug dosing. The gastric pH was measured under each condition for up to 7 h, and the exposure of the compounds tested was calculated. The average gastric pH in fasted dogs ranged from 1.45 to 3.03. Pentagastrin or betaine HCl treatments lowered the pH and reduced its variability between dogs compared to control animals. In contrast, famotidine treatment maintained gastric pH at values close to 7 for up to 5 h, while betaine HCl transiently reduced the pH to approximately 2 in the famotidine-treated dogs. Famotidine pretreatment lowered GDC-0941 exposure by 5-fold, and decreased dasatinib measurable concentrations 30-fold, compared to the pentagastrin-treated dogs. Betaine HCl restored GDC-0941 AUC in famotidine-treated dogs to levels achieved in control animals, and increased dasatinib AUC to 1.5-fold that measured in control dogs. The results confirmed the negative impact of acid-reducing agents on the absorption of weakly basic drugs. They also suggested that betaine HCl coadministration may be a viable strategy in humans treated with acid-reducing agents in order to temporarily reduce gastric pH and restore drug exposure

Design of Selective Benzoxazepin PI3Kδ Inhibitors Through Control of Dihedral Angles

A novel selective benzoxazepin inhibitor of PI3Kδ has been discovered. Beginning from compound <b>3</b>, an αPI3K inhibitor, we utilized structure-based drug design and computational analysis of dihedral torsion angles to optimize for PI3Kδ isoform potency and isoform selectivity. Further medicinal chemistry optimization of the series led to the identification of <b>24</b>, a highly potent and selective inhibitor of PI3Kδ

Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR

Inhibition of phosphoinositide 3-kinase (PI3K) signaling is an appealing approach to treat brain tumors, especially glioblastoma multiforme (GBM). We previously disclosed our successful approach to prospectively design potent and blood–brain barrier (BBB) penetrating PI3K inhibitors. The previously disclosed molecules were ultimately deemed not suitable for clinical development due to projected poor metabolic stability in humans. We, therefore, extended our studies to identify a BBB penetrating inhibitor of PI3K that was also projected to be metabolically stable in human. These efforts required identification of a distinct scaffold for PI3K inhibitors relative to our previous efforts and ultimately resulted in the identification of GDC-0084 (<b>16</b>). The discovery and preclinical characterization of this molecule are described within

Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of Na_V1.7 with Efficacy in Rodent Pain Models

We report on a novel series of aryl sulfonamides that act as nanomolar potent, isoform-selective inhibitors of the human sodium channel hNa_V1.7. The optimization of these inhibitors is described. We aimed to improve potency against hNa_V1.7 while minimizing off-target safety concerns and generated compound <b>3</b>. This agent displayed significant analgesic effects in rodent models of acute and inflammatory pain and demonstrated that binding to the voltage sensor domain 4 site of Na_V1.7 leads to an analgesic effect <i>in vivo</i>. Our findings corroborate the importance of hNa_V1.7 as a drug target for the treatment of pain

The Rational Design of Selective Benzoxazepin Inhibitors of the α‑Isoform of Phosphoinositide 3‑Kinase Culminating in the Identification of (<i>S</i>)‑2-((2-(1-Isopropyl‑1<i>H</i>‑1,2,4-triazol-5-yl)-5,6-dihydrobenzo[<i>f</i>]imidazo[1,2‑<i>d</i>][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326)

Inhibitors of the class I phosphoinositide 3-kinase (PI3K) isoform PI3Kα have received substantial attention for their potential use in cancer therapy. Despite the particular attraction of targeting PI3Kα, achieving selectivity for the inhibition of this isoform has proved challenging. Herein we report the discovery of inhibitors of PI3Kα that have selectivity over the other class I isoforms and all other kinases tested. In GDC-0032 (<b>3</b>, taselisib), we previously minimized inhibition of PI3Kβ relative to the other class I insoforms. Subsequently, we extended our efforts to identify PI3Kα-specific inhibitors using PI3Kα crystal structures to inform the design of benzoxazepin inhibitors with selectivity for PI3Kα through interactions with a nonconserved residue. Several molecules selective for PI3Kα relative to the other class I isoforms, as well as other kinases, were identified. Optimization of properties related to drug metabolism then culminated in the identification of the clinical candidate GDC-0326 (<b>4</b>)

Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice

A series of trisubstituted hydroxylactams was identified as potent enzymatic and cellular inhibitors of human lactate dehydrogenase A. Utilizing structure-based design and physical property optimization, multiple inhibitors were discovered with <10 μM lactate IC₅₀ in a MiaPaca2 cell line. Optimization of the series led to <b>29</b>, a potent cell active molecule (MiaPaca2 IC₅₀ = 0.67 μM) that also possessed good exposure when dosed orally to mice

Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of <i>N</i>‑([1,2,4]Triazolo[4,3‑<i>a</i>]pyridin-3-yl)methane-sulfonamides as Potent and Selective <i>h</i>Na_V1.7 Inhibitors for the Treatment of Pain

The sodium channel Na_V1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation of its role in nociception. In recent years, a number of aryl and acyl sulfonamides have been reported as potent inhibitors of Na_V1.7, with high selectivity over the cardiac isoform Na_V1.5. Herein, we report on the discovery of a novel series of <i>N</i>-([1,2,4]­triazolo­[4,3-<i>a</i>]­pyridin-3-yl)­methanesulfonamides as selective Na_V1.7 inhibitors. Starting with the crystal structure of an acyl sulfonamide, we rationalized that cyclization to form a fused heterocycle would improve physicochemical properties, in particular lipophilicity. Our design strategy focused on optimization of potency for block of Na_V1.7 and human metabolic stability. Lead compounds <b>10</b>, <b>13</b> (GNE-131), and <b>25</b> showed excellent potency, good <i>in vitro</i> metabolic stability, and low <i>in vivo</i> clearance in mouse, rat, and dog. Compound <b>13</b> also displayed excellent efficacy in a transgenic mouse model of induced pain

Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of <i>N</i>‑([1,2,4]Triazolo[4,3‑<i>a</i>]pyridin-3-yl)methane-sulfonamides as Potent and Selective <i>h</i>Na_V1.7 Inhibitors for the Treatment of Pain

The sodium channel Na_V1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation of its role in nociception. In recent years, a number of aryl and acyl sulfonamides have been reported as potent inhibitors of Na_V1.7, with high selectivity over the cardiac isoform Na_V1.5. Herein, we report on the discovery of a novel series of <i>N</i>-([1,2,4]­triazolo­[4,3-<i>a</i>]­pyridin-3-yl)­methanesulfonamides as selective Na_V1.7 inhibitors. Starting with the crystal structure of an acyl sulfonamide, we rationalized that cyclization to form a fused heterocycle would improve physicochemical properties, in particular lipophilicity. Our design strategy focused on optimization of potency for block of Na_V1.7 and human metabolic stability. Lead compounds <b>10</b>, <b>13</b> (GNE-131), and <b>25</b> showed excellent potency, good <i>in vitro</i> metabolic stability, and low <i>in vivo</i> clearance in mouse, rat, and dog. Compound <b>13</b> also displayed excellent efficacy in a transgenic mouse model of induced pain

Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of <i>N</i>‑([1,2,4]Triazolo[4,3‑<i>a</i>]pyridin-3-yl)methane-sulfonamides as Potent and Selective <i>h</i>Na_V1.7 Inhibitors for the Treatment of Pain

The sodium channel Na_V1.7 has emerged as a promising target for the treatment of pain based on strong genetic validation of its role in nociception. In recent years, a number of aryl and acyl sulfonamides have been reported as potent inhibitors of Na_V1.7, with high selectivity over the cardiac isoform Na_V1.5. Herein, we report on the discovery of a novel series of <i>N</i>-([1,2,4]­triazolo­[4,3-<i>a</i>]­pyridin-3-yl)­methanesulfonamides as selective Na_V1.7 inhibitors. Starting with the crystal structure of an acyl sulfonamide, we rationalized that cyclization to form a fused heterocycle would improve physicochemical properties, in particular lipophilicity. Our design strategy focused on optimization of potency for block of Na_V1.7 and human metabolic stability. Lead compounds <b>10</b>, <b>13</b> (GNE-131), and <b>25</b> showed excellent potency, good <i>in vitro</i> metabolic stability, and low <i>in vivo</i> clearance in mouse, rat, and dog. Compound <b>13</b> also displayed excellent efficacy in a transgenic mouse model of induced pain

Discovery of Novel PI3-Kinase δ Specific Inhibitors for the Treatment of Rheumatoid Arthritis: Taming CYP3A4 Time-Dependent Inhibition

PI3Kδ is a lipid kinase and a member of a larger family of enzymes, PI3K class IA­(α, β, δ) and IB (γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3Kδ inhibitors and describe a structural hypothesis for isoform (α, β, γ) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization