Discovery of a series of 2-(1H-pyrazol-1-yl)pyridines as ALK5 inhibitors with potential utility in the prevention of dermal scarring

siRNA-Targeting Transforming Growth Factor-β Type I Receptor Reduces Wound Scarring and Extracellular Matrix Deposition of Scar Tissue

“…Our in vitro results suggest that our in vivo results are due to silencing of TGFBRI expression, leading to the repression of TGF-b/Smad signaling, and finally to a decrease in cell proliferation and ECM deposition in hHSF. The current study shows that the effect of TGFBRI siRNA is similar to that of a TGFBRI inhibitor in scar prevention (Boys et al, 2012). These results indicate that TGFBRI has a critical role in hypertrophic scarring and adequately explain high expression levels of TGFBRI in fibroblasts derived from hypertrophic scars (Schmid et al, 1998;Chin et al, 2001).…”

Dynamics of Transforming Growth Factor Beta Signaling in Wound Healing and Scarring

“…A recent study reported the discovery of a series of small molecules known as 2-(1H-pyrazol-1-yl)pyridines that act as potent ALK5 kinase inhibitors and have demonstrated their potential utility in the prevention of dermal scarring. 160 Topical application of one of these compounds (PF-03671148) in a rat incisional wound repair model led to a reduction in fibrotic gene expression without altering the normal wound healing process. 160 Although these studies are promising, it remains to be seen whether any of these ALK5 inhibitors will be of clinical use, as none of them have yet been screened in Phase I clinical trials for safety and tolerability.…”

Novel Quinazolinone Inhibitors of ALK2 Flip between Alternate Binding Modes: Structure–Activity Relationship, Structural Characterization, Kinase Profiling, and Cellular Proof of Concept

“… 14 Interestingly, PF-03671148 has been shown to be selective against ALK1 likely due a larger gate keeper (Thr) causing a clash with the pyridine substituent. 13 Given that ALK2 also features a threonine gatekeeper residue (Thr283), it is also unlikely to be potently inhibited by PF-03671148 .…”

“…1 H NMR (500 MHz, CDCl 3 /MeOD) δ 8.78 (dd, J = 4.2, 1.7 Hz, 1H), 8.30 (d, J = 1.8 Hz, 1H), 8.14 (ddd, J = 8.6, 1.8, 1.0 Hz, 1H), 8.10 (d, J = 1.4 Hz, 1H), 8.04 (dt, J = 8.5, 1.1 Hz, 1H), 7.78 (dd, J = 8.3, 2.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.72 (dd, J = 8.6, 7.1 Hz, 1H), 7.49 (dd, J = 7.1, 1.3 Hz, 1H), 7.34 (ddd, J = 8.7, 4.3, 1.3 Hz, 1H), 3.56 (d, J = 1.4 Hz, 3H). 13 C NMR (126 MHz, CDCl 3 /MeOD) δ 161.58, 149.90, 147.74, 147.49, 147.29, 138.73, 138.44, 136.10, 134.47, 129.30, 128.63, 127.92, 127.44, 127.29, 126.47, 121.74, 121.45, 34.11. HRMS (ESI) m / z calc C 18 H 14 N 3 O [M + H] + 288.1132; found = 288.113.…”