Tricyclic-Carbocyclic RORγt Inverse Agonists—Discovery of BMS-986313

Abstract

SAR efforts directed at identifying RORγt inverse agonists structurally different from our clinical compound 1 (BMS-986251) led to tricyclic-carbocyclic analogues represented by 3−7 and culminated in the identification of 3d (BMS-986313), with structural differences distinct from 1. The X-ray co-crystal structure of 3d with the ligand binding domain of RORγt revealed several key interactions, which are different from 1. The in vitro and in vivo PK profiles of 3d are described. In addition, we demonstrate robust efficacy of 3d in two preclinical models of psoriasisthe IMQ-induced skin lesion model and the IL-23-induced acanthosis model. The efficacy seen with 3d in these models is comparable to the results observed with 1.

Azatricyclic Inverse Agonists of RORγt That Demonstrate Efficacy in Models of Rheumatoid Arthritis and Psoriasis

“…More recent work has identified the carbocyclic 2,3,3a,4,5,9b-hexahydro-1 H -cyclopenta­[ a ]­naphthalene series as an interesting alternative to the hexahydrobenzoindole core . Compounds 2 and 3a are leading examples from this series, and 3a (BMS-986313) was an advanced preclinical candidate …”

“…Having selected 5 as representing the favorable position for aza substitution, attention was turned to the subsequently discovered hexahydro-1 H -cyclopenta­[ a ]­naphthalene series represented by 2 and 3 . Although 3a was a very appealing compound, we speculated whether further improvements could be made by incorporation of the ring nitrogen to provide the corresponding hexahydro-cyclopentaquinoline core. In particular, we hoped to improve the hWB potency of the former series, while maintaining or improving the in vitro profile with respect to metabolic stability, bioavailability, and selectivity.…”

“…Three analogs of this new core, 8a – 8c (Figure ) were initially prepared and evaluated to allow a matched-pair comparison with the previously described series represented by 3a – 3c . Results of in vitro screening are shown in Table .…”

“…14 Compounds 2 and 3a are leading examples from this series, and 3a (BMS-986313) was an advanced preclinical candidate. 15 Heteroatom replacement (O or N) at the benzylic position of the saturated ring in structure 1 had been previously examined and was found to have negligible effect on potency, 9 despite a reduction in lipophilicity. For example, the calculated log P 16 of chromane 4 (2.38; Figure 2) is an order of magnitude lower than that of 1b (3.18).…”

“…Three analogs of this new core, 8a−8c (Figure 2) were initially prepared and evaluated to allow a matched-pair comparison with the previously described series represented by 3a−3c. 15 Results of in vitro screening are shown in Table 2. As was seen for the hexahydropyrrolo[3,2-f ]quinoline series 5, introduction of a nitrogen atom at position X of the fused benzene ring resulted in a significant increase in the free fraction in serum and a generally modest decrease in CYP inhibition.…”