RPT193, an oral, second-generation CCR4 inhibitor from RAPT Therapeutics, is in Ph. II clinical trials (400 mg QD) to treat atopic dermatitis (AD) (NCT05399368) and asthma (NCT05935332). CCR4 has been a long outstanding therapeutic target for treating inflammatory diseases, but despite many efforts, no molecule inhibiting this receptor has progressed beyond Ph. I for these indications.

Context. Sebetralstat (KalVista Pharmaceuticals) is an oral, on-demand plasma kallikrein (PKa) inhibitor intended for hereditary angioedema (HAE). As an on-demand medication, it can be administered to treat acute attacks rather than chronically to prevent attacks. Its structure was first disclosed at the ACS Spring Meeting earlier this year [...]

The Biocryst oral plasma kallikrein inhibitor, berotralstat (BCX7353) , was recently approved as the first non-steroidal treatment for prevention of hereditary angioedema attacks. The molecule is given orally (150 mg QD) despite having two basic amines. Interestingly for a chronically administered drug, the molecule is noted to have QT [...]

The AstraZeneca oral RORgt inverse agonist, AZD0284 , is an inverse agonist of the nuclear receptor RORC2 (RORγt). Reviewer Chris Gampe says, “targeting the activation and function of Th17 cells has been successful for the treatment of autoimmune disease (cf. IL-17, IL-17R, IL-23 Abs). RORC2 is the transcription factor that controls Th17 [...]

The Eternity Bioscience/Shanghai Hengrui RORγ antagonist, SHR168442, is a skin-restricted, topical compound intended to treat psoriasis. As a master regulator of Th17 immune cells which are significantly involved in allergic diseases, both positive and negative oral modulators of RORγt had been hotly pursued, though many have ceased clinical [...]

The Boehringer RORγ antagonist, BI 730357, is an oral once-daily clinical candidate from a new compound class in development for plaque psoriasis. We highlighted two other RORγ modulators last year in February and March. While most clinical RORγ modulators have discontinued development after reaching Ph. II, BI 730357’s Ph. II trial appears [...]

LEO 39652 (LEO Pharma “dual-soft” topical PDE4 inhibitor soft drug clinical candidate)

BAY 1003803 is a potent topical agonist of the glucocorticoid receptor (GR) transrepression pathway, with less activity on the GR transactivation pathway mediated by GR dimers, which may lead to undesirable side effects. The fluoroaminoquinoline was the only heterocycle among analogs tested that was Ames-negative. The compound appears to have [...]

JTE-052 (delgocitinib) is a pan-JAK kinase inhibitor approved as a topical ointment for treatment of atopic dermatitis in Japan. The compound has an interesting azetidine-containing diazaspirocycle core and a relatively high sp3-fraction for a kinase inhibitor.

BMS-986251 is an inverse agonist of RORgt, a hot target in inflammation for a significant period. Unfortunately it looks like development hit a wall in this space, and several publications of various company’s RORgt modulators have appeared in the last several months. Chemically, 251 is interesting with 5 stereocenters, none of which look [...]

Remibrutinib (Novartis oral BTK-selective covalent kinase inhibitor clinical candidate)